To investigate the effect of a high-fat diet on pharmacokinetics/renal function/RAAS-related parameters after a single dose of empagliflozin in healthy Chinese adults

To investigate the effect of a high-fat diet on pharmacokinetics/renal function/RAAS-related parameters after a single dose of empagliflozin in healthy Chinese adults | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article To investigate the effect of a high-fat diet on pharmacokinetics/renal function/RAAS-related parameters after a single dose of empagliflozin in healthy Chinese adults Yi Jin, Wenyan Zhao, Qian Li, Sunqi Ding, Shuangshuang Tian, Zhaodi Han, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7748740/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Feb, 2026 Read the published version in BMC Pharmacology and Toxicology → Version 1 posted 12 You are reading this latest preprint version Abstract Objectives Literature showed that a high-fat diet (HFD) has an opposite effect on the pharmacokinetic (PK) parameters of empagliflozin (EMPA). EMPA combined with renin-angiotensin-aldosterone system(RAAS)inhibitors is widely used for the treatment of chronic kidney disease. In this study, we investigated the effects of HFD on the PK of EMPA, renal function-related parameters (RF-RP), and RAAS-related parameters (RAAS-RP) affected by EMPA. Methods Based on a bioequivalence study in healthy Chinese adults, twenty blood concentration values were obtained before and within 48 h after EMPA administration in the fasting and fed groups. The maximum plasma concentration (C max ), time to reach C max (T max ), and area under the time-concentration curve (AUC) were calculated. Guided by C max and T max , urine and blood samples were collected and glucose, uric acid, blood urea nitrogen, serum creatinine, insulin, urine α1-microglobulin, β2-microglobulin, plasma renin concentration (PRC), angiotensin II, and aldosterone levels were tested. Estimated glomerular filtration rates were calculated. Results The 90% confidence intervals of the geometric mean ratios of fasting T max , C max , and AUC for the fed group were not within the bioequivalence range. After taking EMPA, urine glucose was higher but β2-microglobulin was significantly lower than before taking EMPA (four: P < 0.001) in the two groups, and both indicators exceeded the normal ranges. Fasting administration of EMPA increased PRC (P < 0.05) but had no effect on aldosterone levels. Other indicators before and after EMPA administration in both groups were within the normal ranges. Conclusions HFD affected the PK parameters of EMPA; however, no further effects on RF-RP and RAAS-RP were by EMPA. Clinical trial registration ChiCTR2400089102, retrospectively registered in https://www.chictr.org.cn/ on 2 September 2024. empagliflozin high-fat diet pharmacokinetics renal function-related parameters RAAS-related parameters Figures Figure 1 Figure 2 Figure 3 Introduction Sodium-glucose transporter 2 (SGLT2) inhibitors (SGLT2i) are a class of oral hypoglycaemic agents initially approved by the United States Food and Drug Administration for use in patients with type 2 diabetes mellitus (T2DM) [ 1 ] . Currently, several SGLT2i have been approved for clinical use, including dagliflozin, cagliflozin, and empagliflozin (EMPA) [ 2 ] . They can exert a direct blood glucose (blood-GLU) lowering effect by inhibiting renal SGLT2, and thus inhibiting glucose reabsorption in the kidneys; and this effect is not dependent on insulin [ 3 ] . EMPA is the representative drug for SGLT2i and used mainly in the 10 mg and 25 mg dosage forms clinically [ 4 , 5 ] . The transit and absorption of drugs in the gastrointestinal tract may differ depending on food intake or fasting. Food consumption produces different physiological changes such as fluctuations in gastric and intestinal pH, delayed gastric emptying, increased bile secretion, and visceral blood flow [ 6 ] . The physiological changes induced by a modified diet can influence the efficacy of several drugs, mainly by affecting pharmacokinetic (PK) mechanisms [ 7 ] . Managing drug-food interactions is essential for optimizing the PK parameters, safety profile, and effectiveness of EMPA. A literature analysis showed that PK studies of a single dose of EMPA administration in the postprandial versus fasting state in healthy subjects were currently available in a total of six studies, three of which were conducted with 25 mg, two with 10 mg, and one with 50 mg separately [ 8 – 13 ] . Due to differences in dosage and experimental protocols, the main parameters of PK [ 14 ] , including maximum plasma concentration (C max ), time to reach C max (T max ), and area under time-concentration curve (AUC) of the above studies, exhibited distinct characteristics. Two PK studies of 10 mg EMPA in different countries involving healthy participants showed opposite trends in PK parameters after fasting and consumption of a high-fat diet (HFD) [ 11 , 13 ] . Based on the above literature analysis, we first studied the effect of an HFD on the PK parameters of 10 mg EMPA in healthy Chinese adults. In addition to lowering blood-GLU levels, EMPA improves renal outcomes in patients with chronic kidney disease (CKD), including those with diabetic kidney disease (DKD) and non-DKD. Several studies have explored renal function-related pharmacodynamic (PD) parameters of EMPA, including blood urea nitrogen (BUN) and serum creatinine (SCr) [ 15 ] . On the other hand, in addition to controlling blood-GLU and blood pressure, blocking the RAAS has been an important intervention for retarding DKD progression for decades [ 16 ] . A new aldosterone synthase inhibitor, used with EMPA, has been reported to not only reduce albuminuria, but also have additional efficacy in the treatment of CKD [ 17 ] . Using the 10 mg EMPA bioequivalence (BE) study, we studied how HFD affected the PK parameters of EMPA and renal function-related PD and RAAS-related parameters after taking EMPA. Renal function-related parameters included blood-GLU, blood uric acid (blood-UA), BUN, SCr, urine glucose (urine-GLU), urine uric acid (urine-UA), urine α1-microglobulin (α1-MG), and urine β2-microglobulin (β2-MG), and RAAS-related parameters included blood renin concentration (PRC), angiotensin II (Ang II), and aldosterone (ALD). Materials and Methods Literature analysis Based on Pubmed, Scoups, Wanfang and CNKI database, the literatures about PK research of EMPA were summarized. The analysis focused on the influence of a HFD on the main PK parameters: C max , T max and AUC. Study design In this study, the influence of HFD on PK/PD/RAAS parameters after EMPA administration was based on a BE study ( https://www.cde.org.cn . Registration No. CTR20232603) in a randomized, open-label, two-period, two-sequence, two-way crossover study under fasting and fed conditions. The BE of two EMPAs was assessed: a generic 10 mg EMPA was as test (EMPA-T) (Sponsor information was not allowed to be displayed under the study agreement), and 10 mg branded Jardiance®, manufactured by the producer Boehringer Ingelheim (Ingelheim, Germany, Batchnumber, 1705039), was as a reference (EMPA-R). All trial-related procedures were performed at the Phase I Clinical Trial Research Center of the Drug Clinical Trial Institution of the Shanxi Provincial People’s Hospital. The study protocol was approved by the Ethics Committee of Shanxi Provincial People’s Hospital and approval Number 2023-045 for the PK study in the BE trial, 2023 − 364 and 2023 − 399 for the PD/RAAS study under fasting and fed conditions, respectively). This study was registered in Chinadrugtrials.org.cn (ChiCTR2400089102). Subjects The subjects in the BE/PK and PD/RAAS study were healthy Chinese volunteers. Before starting the study, medical and laboratory tests were conducted to ensure the health of volunteers. Smokers, heavy drinkers, those who used drugs that affected kidney metabolism within the previous 4 weeks, those who had taken any medicine within the previous 7 days, those who had a history of medication allergies, hypoglycemia or hypotension, those who had participated in previous clinical studies within the previous three months, and those with any significant clinical abnormality were excluded. In accordance with the trial protocol, 30 volunteers were recruited for the study in the fasting group and 30 in the fed group. Empagliflozin administration The day before the study, the participants were asked to avoid eating particular fruits (such as dragon fruit, mango, and grapefruit) and xanthine-rich foods, thus avoiding excessive physical exercise. The participants consumed a uniformly prepared dinner and stopped eating at 10:00 AM. On the day of the study, the subjects in the fasting group were administered one tablet of EMPA with 240 mL of water at 8:00 AM (study time point: 0 h). The fed group was fed a standard HFD 30 min before EMPA administration (Fig. 1 ). The component list of HFD is shown in Supplementary Table 1. Taking subject 1 as an example, he started his first bite at 7:30 AM and completed all meals within 29 min. At 8:00 AM, subject 1 took one tablet of EMPA with 240 mL water. Subsequent subjects, according to their number, at 1-min intervals, started their HFD and took EMPA. No food was allowed for 4 h after the dose, and in addition to ambulation, everyone was in a sitting position. Water (200 mL) was uniformly available for 2 h after the administration. Blood samples of BE/PK measurements Venous blood samples (3 mL per sample) were obtained before administering the medication (0 h) and at 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 4, 6, 8, 10, 12, 24, 36, and 48 h after EMPA administration under both fasting and fed conditions. Samples were centrifuged at 2,500 × g for 10 min, and the serum was extracted and frozen at -60℃ for 60 min. Plasma concentrations of EMPA were detected using LC-MS/MS. Blood samples of PD/RAAS measurements Blood samples were collected three times to measure the PD and RAAS-related indicators. The first time in the fasting group was completed from 7:30 AM to 7:50 AM on the day of the study (i.e., before EMPA administration). In the fed group, the first collection time was from 7:00 AM to 7:20 AM, that is, before the HFD and EMPA administration. The second and the third time was after 2 h and 4 h of taking EMPA, respectively (time points: 2 h and 4 h). All blood samples were centrifuged at 3,800 rpm at 4°C for 8 min. The protocol is illustrated in Fig. 1 . Blood GLU levels were measured using a Beckman Coulter AU5800 fully automatic biochemical analyzer (Beckman Coulter International Trading Co., LTD, USA). Insulin levels were analyzed using chemiluminescent immunoassay (Roche Cobase 601; Roche Diagnostics GmbH, Germany). Renal function-related indicators, including BUN, SCr, and blood UA and RAAS-related indices, including PRC, Ang II, and ALD, were measured using AutoLumo A2000 Plus (Zhengzhou Antu Biological Engineering Co. LTD, China). eGFR was determined using the following formula [ 18 ] . Urine samples of PD measurements Urine samples were collected twice. The first time was after waking up at 6:00 AM and before 8:00 AM on the study day (study period: -2 ~ 0 h). The second administration was within 4 h of EMPA administration (study period, 0 ~ 4 h). Urine from each subject was collected separately on his own in a clean 1,000 mL cylinder. Urine samples (8 mL) were tested for urine-GLU and urine-UA using a Beckman Coulter AU5800 fully automatic biochemical analyzer (Beckman Coulter International Trading Co., LTD, USA). Urine samples (8 mL) were centrifuged at 1,500 rpm at room temperature for 5 min, and the levels of urine α1-MG and β2-MG were measured using an automatic specific protein analyzer, BIOSYSTEM BA400 (Biosystems S.A. Costa Barcelona, Spain). Safety observation Potential adverse events (AEs) and vital signs (systolic and diastolic blood pressure, body temperature, and pulse rate) were assessed throughout the study. AEs were described according to the “Common Terminology Criteria for Adverse Events (version 2025”). Researchers recorded AEs in terms of their seriousness, intensity, time course, outcome, and relationship with the study drug. Statistical Analysis PK parameters included C max , T max , and area under the time-concentration curve from administration to the last observed concentration at time t (AUC 0 ~ t ). area under the time-concentration curve extrapolated to infinity (AUC 0−∞ ). percentage of the residual area of the AUC (AUC _%Extrap ), terminal half-life (t 1/2 ), and elimination rate constant (λ z ). The PK study employed a non-compartmental method using Statistical Analysis System (SAS) version 9.4. Blood concentration-time data were collected after fasting or fed administration. The PK parameters were statistically analyzed. The AUC 0 ~ t for EMPA was calculated using the trapezoidal method. If the 90% CI for the GMR of AUC 0 ~ t , AUC 0~∞ , and C max fell within the statistical range of 80.00% to 125.00% as proposed by the NMPA, then the fasting and fed conditions are considered bioequivalent [ 19 ] . The PD/RAAS statistical analysis was performed using SPSS 22.0. Due to the small sample size (n < 30), the Shapiro-Wilk test was used to analyze all variables for normal distribution. Data that conformed to the normal distribution were analyzed using the Mann-Whitney U test, while data that did not conform were analyzed using the independent rank sum test. All continuous variable data are expressed as the mean ± standard deviation. All reported P values were two-tailed, and statistical significance was set at P < 0.05. Results Literature analysis Supplementary Fig. 1 shows that the five PK studies, including 25 mg EMPA and 10 mg EMPA, were based on the BE study, and the other 50 mg study was based on the original EMPA data. To analyze whether HFD had effects of HFD on the PK parameters, we compared four studies in which EMPA was performed using warm water. The results of three studies showed that HFD decreased both C max and AUC, which were conducted at doses of 10, 25, and 50 mg, whereas another study on 10 mg showed the opposite result, that is, HFD increased both C max and AUC of EMPA. In these two studies on 10 mg EMPA, one showed that Jordanian participants had an increase in the mean C max and AUC of approximately 50% to 74% after consuming HFD, and another showed that the average C max of Chinese volunteers dropped to 80.8% after consuming HFD. The participants included in the analysis Of the 30 volunteers enrolled in the fasting group, one subject withdrew due to syncope before the first period of administration, and the other two subjects withdrew at the second period. In the HFD group, one voluntarily withdrew after the end of the first period and one did not complete HFD at the second period. According to the sensitivity analysis, the plasma concentrations of the participants included in the PK parameter set and the BE set for analysis were as follows: EMPA-R (n = 28) and EMPA-T (n = 28) in the fasting group and EMPA-R (n = 29) and EMPA-T (n = 29) in the fed group (Table 1 ). Table 1 Participants Situations of the participants Fasting group Fed group The enrolled participants n = 30 n = 30 The participants who withdrew or dropped out EMPA-T and EMPA-R: n = 1 EMPA-T: n = 1 EMPA-R: n = 1 EMPA-T: n = 1 EMPA-R: n = 1 The participants who included in the analysis EMPA-R: n = 28 EMPA-T: n = 28 EMPA-R: n = 29 EMPA-T: n = 29 Notes: EMPA-R, a branded empagliflozin was as the reference. EMPA-T, a generic empagliflozin was the test. Our research confirmed that the 90% CI for the GMR of AUC 0 ~ t , AUC 0~∞ , and C max was within the statistical range of 80.00%~125.00% when 10 mg EMPA-T was compared to EMPA-R under fasting (Supplementary Table 2) and fed conditions (Supplementary Table 3). In the study of the effect of HFD on PK parameters, the plasma concentrations included in the analysis were as follows: fasting group (n = 56, EMPA-R (n = 28) and EMPA-T (n = 28)) and fed group (n = 58: EMPA-R (n = 29) and EMPA-T (n = 29)) according to the sensitivity analysis. Table 1 lists these details. In the PD/RAAS study, 42 healthy subjects signed an informed consent form (fasting, n = 19; fed, n = 23) and completed the entire study. The influence of HFD on plasma concentrations Table 2 shows plasma concentrations at 20 blood sampling points before and 48 h after EMPA administration. A total of 18 time points had higher concentrations in the fasting than in the fed from 0.25 h to 36 h, with 16 points significantly different, clustered between 0.25 h and 12 h (all: P < 0.01). At 0.25 h after dosing, the plasma concentration ratio of fasting to fed was highest at 3.3-fold, followed by 3.0-fold at 0.5 h and 2.3-fold at 1 h. Table 2 Comparisons of plasma concentrations Serial number Time points of sampling (h) Plasma concentrations (ng/mL) CV of the plasma concentrations (%) Fasting (n = 56) Fed (n = 58) P value Fasting/fed Fasting (n = 56) Fed (n = 58) 1 0 BQL BQL / / / / 2 0.25 26.9 ± 31.9 8.2 ± 13.4 < 0.001 * 3.28 118.45 162.73 # 3 0.5 102.6 ± 61.0 34.2 ± 31.0 < 0.001 * 3.00 59.44 90.61 # 4 1 165.7 ± 60.6 72.9 ± 49.5 < 0.001 * 2.27 36.59 67.83 # 5 1.25 167.5 ± 44.1 87.4 ± 39.2 < 0.001 * 1.92 26.34 44.90 # 6 1.5 163.2 ± 35.6 95.7 ± 33.7 < 0.001 * 1.71 21.83 35.25 # 7 1.75 157.9 ± 32.4 94.1 ± 28.1 < 0.001 * 1.68 20.49 29.86 # 8 2 151.8 ± 27.3 94.2 ± 26.3 < 0.001 * 1.61 18.02 27.88 # 9 2.25 148.2 ± 28.2 91.5 ± 22.6 < 0.001 * 1.62 19.02 24.71 # 10 2.5 138.0 ± 21.9 85.3 ± 18.8 < 0.001 * 1.62 15.86 22.05 # 11 2.75 130.5 ± 18.5 83.9 ± 16.0 < 0.001 * 1.55 14.18 19.04 # 12 3 123.3 ± 17.9 79.4 ± 15.0 < 0.001 * 1.55 14.55 18.86 # 13 4 104.4 ± 16.4 74.4 ± 11.1 < 0.001 * 1.40 15.73 14.92 14 6 72.0 ± 12.5 53.1 ± 8.8 < 0.001 * 1.36 17.39 16.57 15 8 52.6 ± 9.1 40.5 ± 7.6 < 0.001 * 1.30 17.28 18.77 # 16 10 40.4 ± 8.2 32.7 ± 6.7 0.002 * 1.24 20.42 20.60 # 17 12 30.7 ± 6.5 25.4 ± 4.9 0.004 * 1.21 21.20 19.43 18 24 10.1 ± 3.0 9.3 ± 1.8 0.281 1.09 29.27 19.63 19 36 3.5 ± 1.4 3.2 ± 1.2 0.483 1.09 39.44 35.97 20 48 2.2 ± 0.9 2.2 ± 0.8 0.839 1.03 40.19 34.66 Notes: * P < 0.01, plasma concentration of the fasting vs the fed. # CV of the fed was higher than that of the fasting. CV, coefficient of variation. Table 2 Comparisons of plasma concentrations Notes: * P < 0.01, plasma concentration of the fasting vs the fed. # CV of the fed was higher than that of the fasting. CV, coefficient of variation. Serial number Time points of sampling (h) Plasma concentrations (ng/mL) CV of the plasma concentrations (%) Fasting (n = 56) Fed (n = 58) P value Fasting/fed Fasting (n = 56) Fed (n = 58) 1 0 BQL BQL / / / / 2 0.25 26.9 ± 31.9 8.2 ± 13.4 < 0.001 * 3.28 118.45 162.73 # 3 0.5 102.6 ± 61.0 34.2 ± 31.0 < 0.001 * 3.00 59.44 90.61 # 4 1 165.7 ± 60.6 72.9 ± 49.5 < 0.001 * 2.27 36.59 67.83 # 5 1.25 167.5 ± 44.1 87.4 ± 39.2 < 0.001 * 1.92 26.34 44.90 # 6 1.5 163.2 ± 35.6 95.7 ± 33.7 < 0.001 * 1.71 21.83 35.25 # 7 1.75 157.9 ± 32.4 94.1 ± 28.1 < 0.001 * 1.68 20.49 29.86 # 8 2 151.8 ± 27.3 94.2 ± 26.3 < 0.001 * 1.61 18.02 27.88 # 9 2.25 148.2 ± 28.2 91.5 ± 22.6 < 0.001 * 1.62 19.02 24.71 # 10 2.5 138.0 ± 21.9 85.3 ± 18.8 < 0.001 * 1.62 15.86 22.05 # 11 2.75 130.5 ± 18.5 83.9 ± 16.0 < 0.001 * 1.55 14.18 19.04 # 12 3 123.3 ± 17.9 79.4 ± 15.0 < 0.001 * 1.55 14.55 18.86 # 13 4 104.4 ± 16.4 74.4 ± 11.1 < 0.001 * 1.40 15.73 14.92 14 6 72.0 ± 12.5 53.1 ± 8.8 < 0.001 * 1.36 17.39 16.57 15 8 52.6 ± 9.1 40.5 ± 7.6 < 0.001 * 1.30 17.28 18.77 # 16 10 40.4 ± 8.2 32.7 ± 6.7 0.002 * 1.24 20.42 20.60 # 17 12 30.7 ± 6.5 25.4 ± 4.9 0.004 * 1.21 21.20 19.43 18 24 10.1 ± 3.0 9.3 ± 1.8 0.281 1.09 29.27 19.63 19 36 3.5 ± 1.4 3.2 ± 1.2 0.483 1.09 39.44 35.97 20 48 2.2 ± 0.9 2.2 ± 0.8 0.839 1.03 40.19 34.66 Within 3 h after administration, the plasma concentration variability in the fed group, expressed as the coefficient of variation (CV), was higher than that in the fasting group, suggesting that the HFD may affect the absorption of EMPA among individuals [ 20 ] . The influence of HFD on PK parameters The calculated PK parameters, including T max , C max , AUC 0 ~ t , AUC 0~∞ , AUC _%Extrap , t 1/2 and λ z are presented in Table 3 . Table 3 Comparisons of pharmacokinetic parameters Notes: C max , maximum plasma concentration. T max , time to reach C max . AUC 0 ~ t , area under time-concentration curve from administration to last observed concentration at time t. AUC 0−∞ , area under time-concentration curve from administration extrapolated to infinity. AUC_ %Extrap , percentage of residual area of AUC. t 1/2 , terminal half-life. λ z , elimination rate constant. CI, confidence interval. Parameters Units Geometric mean and ratio 90%CI of the ratio (%) Fasting Fed Fasting/Fed (%) T max h 1.31 1.67 78.44 49.05 ~ 107.46 C max ng/mL 186.70 112.79 165.53 152.29 ~ 178.77 AUC 0 − t ng·h/mL 1305.15 950.93 137.25 127.21 ~ 147.29 AUC 0−∞ ng·h/mL 1331.45 977.89 136.16 125.86 ~ 146.45 AUC_% Extrap % 1.80 2.57 70.04 44.06 ~ 96.16 t 1/2 h 8.18 8.34 98.08 85.81 ~ 110.26 λ z 1/hr 0.08 0.08 100.00 96.41 ~ 107.58 Table 3 Comparisons of pharmacokinetic parameters Parameters Units Geometric mean and ratio 90%CI of the ratio (%) Fasting Fed Fasting/Fed (%) T max h 1.31 1.67 78.44 49.05 ~ 107.46 C max ng/mL 186.70 112.79 165.53 152.29 ~ 178.77 AUC 0 − t ng·h/mL 1305.15 950.93 137.25 127.21 ~ 147.29 AUC 0−∞ ng·h/mL 1331.45 977.89 136.16 125.86 ~ 146.45 AUC_% Extrap % 1.80 2.57 70.04 44.06 ~ 96.16 t 1/2 h 8.18 8.34 98.08 85.81 ~ 110.26 λ z 1/hr 0.08 0.08 100.00 96.41 ~ 107.58 Notes: C max , maximum plasma concentration. T max , time to reach C max . AUC 0 ~ t , area under time-concentration curve from administration to last observed concentration at time t. AUC 0−∞ , area under time-concentration curve from administration extrapolated to infinity. AUC_ %Extrap , percentage of residual area of AUC. t 1/2 , terminal half-life. λ z , elimination rate constant. CI, confidence interval. The GMR for T max , C max , AUC 0 ~ t , AUC 0~∞ and AUC _%Extrap between the fasting and the fed were 78.44%, 165.53%, 137.25%, 136.16% and 70.04%, respectively, and their corresponding 90% CI were (49.05 ~ 107.46)%, (152.29 ~ 178.77)%, (127.21 ~ 147.29)%, (125.86 ~ 146.45)% and (44.06 ~ 96.16)%, respectively, which were not within the bioequivalent range (80.00 ~ 125.00)% [ 21 , 22 ] , suggesting that HFD delayed T max and decreased C max and AUC of 10 mg EMPA. The influence of HFD on PD parameters The results for urine-GLU, urine-UA, insulin, blood-GLU, and blood-UA levels are shown in Figs. 2 A ~ 2E. As shown in Fig. 2 A, the urine-GLU levels in the fasting and fed groups within 4 h of EMPA administration were significantly higher than those before administration (two: P < 0.001). Additionally, within 4 h after EMPA administration, the fed group exhibited a significantly higher urine GLU level than the fasting group (P = 0.024). From Fig. 2 C and 2 D, we can see that after 2 h and 4 h of EMPA administration in the fasting group, the fasting blood-GLU and insulin levels were significantly decreased (four: P < 0.001). However, the decreased fasting blood-GLU and insulin levels were still within normal ranges. From Figs. 2 B and 2 E, it can also be seen that after EMPA administration, the trend of blood-UA decreased with an increase in urine-UA excretion, which only showed a significant difference in the fed group (two: P < 0.001). The results for SCr, BUN, and eGFR are shown in Figs. 2 F ~ 2H. In the fed group, 2 h and 4 h after taking EMPA, compared with before taking EMPA, there were significant differences on the SCr, BUN, and eGFR levels (six: P < 0.05). In the fasting group, there was a significant difference in BUN between 2 and 4 h after administration of EMPA alone for BUN compared to before taking the medicine (two: P < 0.05). After the administration of EMPA in the fasting and fed groups, the above three indicators were also within the normal range. The results for the two urinary microglobulins α1-MG and β2-MG are shown in Figs. 2 I and 2 J. In the fasting group, both urinary α1-MG and β2-MG levels significantly decreased after EMPA administration compared to those before EMPA administration (P = 0.005 and P = 0.017, respectively). In the fed group, the EMPA intervention significantly reduced urinary β2-MG levels (P < 0.001), which exceeded the normal range. The influence of HFD on RAAS-related parameters The levels of PRC and Ang II in the fasting group were significantly higher than those before EMPA administration when EMPA was administered for 2 and 4 h (four: P < 0.05), and the increased PRC levels were higher than the upper limit of normal. However, there was no significant change in ALD levels. Compared with before EMPA administration, PRC, Ang II, and ALD showed a downward trend in the fed group 4 h after EMPA administration, and there were significant differences in PRC and Ang II (four: P < 0.05). The results are shown in Fig. 3 A, 3 B, and 3 C. Safety observation The AEs observed in this study are listed in Table 4 . The overall incidence of AEs in the fasting and fed groups was 14.3% and 13.8%, respectively. There were no significant differences between the two incidence rates. Table 4 Adverse events Descriptions of adverse events * Fasting (n = 56) Fed (n = 58) Numbers Time of occurrence # Numbers Time of occurrence # Decreased diastolic blood pressure 1 4 h 1 4 h Dizziness 1 6 h 0 / Nausea 1 27 h 0 / Decreased fasting blood glucose 0 / 0 / Urinary tract infection 2 48 h 2 48 h Hypertriglyceridemia 1 48 h 1 48 h Increased serum creatinine 1 48 h 0 / Elevated low-density lipoprotein cholesterol 1 48 h 1 48 h Elevated alanine aminotransferase 0 / 1 48 h Elevated γ-glutamyltranspeptidase 0 / 2 48 h Total 8 / 8 / Notes: * All descriptions of adverse events were according to “Common Terminology Criteria for Adverse Events (version 2025)”, with a severity of “Grade 1”, and all outcomes were “recovered”. # The time after taking empagliflozin. The most reported AE in both groups was urinary tract infection, with 2 cases in each group. The AEs observed in both groups included decreased diastolic blood pressure, hypertriglyceridemia, and elevated low-density lipoprotein cholesterol levels. AEs reported only in the fasting group included dizziness, nausea, and elevated serum creatinine level. AEs that occurred only in the fed group included elevated alanine aminotransferase and γ-glutamyl transpeptidase levels. All of the above AEs were described in the instructions for Jardiance® and were Grade 1 in severity, recovered spontaneously without any intervention, and no subject withdrew from the trial due to AEs. Discussion Lifestyle, including exercise and diet, can alter several physiological functions of the human body. Food intake can cause various physiological changes in the human gastrointestinal tract, such as changes in the gastrointestinal pH, gastric emptying time, and metabolic enzymes [ 7 ] . These changes can affect the PK characteristics of certain drugs by altering their release, absorption, distribution, metabolism, and/or excretion [ 23 ] . PK and PD interactions with food can lead to reduced drug efficacies. This is known as the negative food effect, which refers to a reduction in bioavailability when a drug is ingested [ 24 ] . According to the most previous studies, administering EMPA after HFD resulted in decreases in mean C max and AUC, [ 8 – 12 , 25 ] but there were also individual studies that yielded opposite results [ 13 ] . The HFD used in the aforementioned studies refers to foods with a total calorie intake of (800 ~ 1000) kcal, and calories from fat should provide (500 ~ 600) kcal [ 19 ] . It has been confirmed that HFDs have more significant physiological impacts on the gastrointestinal tract, therefore regulatory authorities recommend using high calorie and high-fat meals in food impact studies [ 26 ] Our study indicated that the HFD used in this study, which provided 934.74 kcal, delayed T max after EMPA administration while reducing C max and AUC, including AUC 0 ~ t and AUC 0~∞ . In healthy subjects, PD drug-drug interactions between EMPA and other hypoglycemic medicines such as evogliptin [ 27 ] , metformin and lobeglitazone [ 28 ] were explored based on the PK properties of EMPA. The effect of food on PK parameters often begins in phase I clinical trials, based on observations in healthy subjects [ 29 ] . With increasing clinical evidence of EMPA in patients with non-DKD, [ 30 ] focusing on the direct effect of EMPA on renal function-related indicators in healthy people may lay a foundation for further exploration of its improvement in patients with CKD. Among the indicators related to kidney function, the first indicator we focused on was the blood-UA level. In a double-blind, randomized, placebo-controlled study, 45 healthy volunteers underwent blood and urine sampling one month after EMPA administration. It was found that their blood-UA levels decreased by 28.4% [ 31 ] . Our results showed a si milar downward trend in blood-UA levels in the above study. Unlike the chronic effects described above, our research showed an acute effect of EMPA on decreasing blood-UA levels in both fasting and fed states. This decrease in blood-UA was associated with an increase in urine-UA [ 32 ] and urine-GLU [ 33 ] levels, which was also observed in this study. More urine-UA and urine-GLU were excreted in the fed group, indicating that EMPA could dynamically regulate blood-GLU, urine-GLU, blood-UA, and urine-UA according to the different states of the body. Taking blood-GLU as an example, it appeared that there was a dynamic balance between the increase in blood-GLU due to HFD and the increase in urine-GLU excretion, which ultimately determined the extent of urine-GLU excretion. A similar balance between the increase in hepatic glucose production and the increase in urine-GLU excretion immediately after SGLT2 inhibition has been observed in a clinical study [ 34 ] . Decreasing effects of EMPA on α1-MG were observed in patients with acute decompensated heart failure and in [ 35 ] , patients with renal proximal tubulopathy in the Fanconi-Bickel syndrome [ 36 ] . Both α1-MG and β2-MG are regarded as markers of renal tubular impairment. Notably, patients with DKD have been found to exhibit higher levels of α1-MG than patients with T2DM [ 37 ] . Children with severe mycoplasma pneumoniae pneumonia-related acute kidney injury (AKI) had higher α1-MG and β2-MG levels than non-AKI children [ 38 ] . Unlike the previous reports, the acute effects of EMPA on decreasing α1-MG and β2-MG levels were also observed in this study in healthy volunteers. It has been suggested that combining RAAS inhibitors and a low-protein diet might be a high-quality intervention to slow CKD progression [ 39 ] . On the other hand, augmenting RAAS inhibitors with new drug classes, such as SGLT2 inhibitor, has the potential to improve clinical outcomes in a broad range of patients with CKD [ 40 ] . To study focused on the effect of EMPA on the RAAS axis in the dietary state. Our results suggest that taking EMPA on an empty stomach in healthy subjects increased the PRC level above the upper limit of normal but ultimately had little effect on the ALD level. If EMPA was administered after a meal, the three indicators on the RAAS axis remained within the normal range. This suggests that HFD plays a limited role. The hypoglycemic mechanism of EMPA is associated with increased urine-GLU excretion [ 41 ] . We observed that a significant reduction in blood-GLU in the fasting group led to a significant decrease in insulin levels at corresponding time points. This might prevent the induction of hypoglycemia [ 42 ] and the safety of EMPA was confirmed by the blood-GLU test results within 4 h of taking EMPA under fasting and fed conditions, which was to maintain the reduced blood-GLU within the normal range without the risk of hypoglycaemia [ 43 ] . In summary, based on the BE study, we discuss the effects of HFD on PK parameters, renal function-related PD parameters, and RAAS-related indicators affected by EMPA in healthy subjects. Our results suggest that although HFD significantly affected the PK parameters of EMPA, it did not affect renal function-related PD parameters and RAAS-related indicators of EMPA. Declarations Acknowledgments The authors thank all the volunteers who participated in this study, Dr. Xiaocheng Wang for providing statistical guidance, and the Ethics Committee for their guidance and supervision. Author Contributions Conceptualization: Yi Jin and Hui Liao; Data curation: Yi Jin and Lu Bai; Formal analysis: Yi Jin and Wenyan Zhao; Funding acquisition: Hui Liao; Investigation, Yi Jin, Wenyan Zhao, Hui Wu and Lu Bai; Methodology, Sunqi Ding and Hui Liao; Project administration: Hui Liao; Resources, Zhaodi Han and Hui Liao; Software, Qian Li and Shuangshuang Tian; Supervision, Hui Liao; Validation, Qian Li and Zhaodi Han; Visualization, Yi Jin and Hui Wu; Writing – original draft: Wenyan Zhao,Sunqi Ding, Qian Li, Shuangshuang Tian and Hui Liao; Writing – review and editing: Wenyan Zhao and Hui Liao. Funding This study was supported by Demonstration Project on Reformation and Quality Development of Public Hospitals (No.SCP-2023-8), the Local Science and Technology Development Funds Projects Guided by Central Government (No. YDZJSX2021C027), Basic Research Program of Shanxi Province (No.202103021224370). Data Availability Some datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request. Ethics approval and consent to participate The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Shanxi Provincial People’s Hospital (BE protocol code: 2023-045, approval date: 27-7-2023, PD protocol code: 2023-364 (fasting) and 2023-399 (fed), approval date:29-8-2023 (fasting) and 28-9-2023 (fed)). Informed Consent Statement Informed consent was obtained from all participants involved in the study. 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Supplementary Files 5.SupplementaryTable1.ComponentslistoftheHFD.docx 6.SupplementaryTable2.BEresultsoffastinggroup.docx 7.SupplementaryTable3.BEresultsoffedgroup.docx 4.SupplementaryFigure1.Literatureanalysis.pdf Cite Share Download PDF Status: Published Journal Publication published 09 Feb, 2026 Read the published version in BMC Pharmacology and Toxicology → Version 1 posted Editorial decision: Revision requested 22 Dec, 2025 Reviews received at journal 02 Dec, 2025 Reviews received at journal 02 Dec, 2025 Reviews received at journal 20 Nov, 2025 Reviewers agreed at journal 12 Nov, 2025 Reviewers agreed at journal 11 Nov, 2025 Reviewers agreed at journal 20 Oct, 2025 Reviewers invited by journal 13 Oct, 2025 Editor invited by journal 07 Oct, 2025 Editor assigned by journal 03 Oct, 2025 Submission checks completed at journal 03 Oct, 2025 First submitted to journal 30 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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15:40:50","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":177569,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/beb73097495e3ca98a327ce7.html"},{"id":94472207,"identity":"9e7ffb58-6d0a-4495-bd0d-93475315fa0f","added_by":"auto","created_at":"2025-10-27 15:40:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":149323,"visible":true,"origin":"","legend":"\u003cp\u003eResearch flow chart\u003c/p\u003e\n\u003cp\u003eNotes: RAAS: Renin-angiotensin-aldosterone system; PK: pharmacokinetics; C\u003csub\u003emax\u003c/sub\u003e: Peak concentration; AUC: Area under time-concentration curve; PD: pharmacodynamics; GLU: glucose; UA: Uric acid; SCr: Serum creatinine; BUN: Blood urea nitrogen; eGFR: Estimated glomerular filtration rate; α1-MG: α1-microglobulin; β2-MG: β2-microglobulin.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/bb3fe54f876c029afbdef6b3.png"},{"id":94471659,"identity":"f4f8942d-c316-4de4-b6d5-cde822dcc0a1","added_by":"auto","created_at":"2025-10-27 15:39:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":381371,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-fat diet on pharmacodynamics parameters of empagliflozin in healthy subjects\u003c/p\u003e\n\u003cp\u003e(A) Urinary glucose (Urine-GLU) levels. (B) Urinary uric acid (Urine-UA) levels. (C) Insulin levels. (D) Blood glucose (Blood-GLU) levels. (E) Blood uric acid (Blood-UA) levels. (F) Serum creatinine (SCr) levels. (G) Blood urea nitrogen (BUN) levels. (H) Estimated glomerular filtration rate (eGFR) levels. (I) α1-microglobulin (α1-MG) levels. (J) β2-microglobulin (β2-MG) levels.\u003c/p\u003e\n\u003cp\u003eNotes: Data are presented as mean ± standard deviation. *P \u0026lt; 0.05, In the fasting group, post-dose (2 h and 4 h) vs. pre-dose (-2~0 h or 0/-1h). #P \u0026lt; 0.05, In the fed group, post-dose (2 h and 4 h) vs. pre-dose (-2~0 h or 0/-1 h). 0/-1 h: before empagliflozin administration. 2 h: 2 h after empagliflozin administration. 4 h: 4 h after empagliflozin administration. -2~0 h: 2 to 0 h before empagliflozin administration. 0~4 h: 0 to 4 h after empagliflozin administration. Fasting group: n = 19. Fed group: n = 23.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/8fb8f3a89c425d7d3022ac85.png"},{"id":94471921,"identity":"e30be2d7-9ece-413d-887b-4acca1a483b7","added_by":"auto","created_at":"2025-10-27 15:40:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":138520,"visible":true,"origin":"","legend":"\u003cp\u003eEffects of high-fat diet on RAAS-related parameters of empagliflozin in healthy subjects\u003c/p\u003e\n\u003cp\u003e(A) Plasma renin concentration (PRC) levels. (B) Angiotensin II (Ang Ⅱ) levels. (C) Aldosterone (ALD) levels.\u003c/p\u003e\n\u003cp\u003eNotes: Data are presented as mean ± standard deviation. \u003csup\u003e*\u003c/sup\u003eP \u0026lt; 0.05, In the fasting group, post-dose (2 h and 4 h) vs. pre-dose (0 h). \u003csup\u003e#\u003c/sup\u003eP \u0026lt; 0.05, In the fed group, post-dose (2 h, and 4 h) vs. pre-dose (0 h). 0 h: before empagliflozin administration; 2h: 2 h after empagliflozin administration. 4 h: 4 h after empagliflozin administration. Fasting group: n = 19; Fed group: n = 23.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/893f420e5911a2ddca45f017.png"},{"id":102785530,"identity":"4a68047d-d04e-4b05-98d3-bd8e99116d1c","added_by":"auto","created_at":"2026-02-16 16:07:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2112919,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/f0502c80-d246-47f9-9ee7-5296a103c1ae.pdf"},{"id":94471915,"identity":"4e6c41c5-d10c-4777-9e3c-1dcf692b08a7","added_by":"auto","created_at":"2025-10-27 15:40:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18195,"visible":true,"origin":"","legend":"","description":"","filename":"5.SupplementaryTable1.ComponentslistoftheHFD.docx","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/b65103a18baf248e43ad9704.docx"},{"id":94471773,"identity":"621e31f7-3f64-425b-956f-f8e4abd380e4","added_by":"auto","created_at":"2025-10-27 15:39:37","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":18826,"visible":true,"origin":"","legend":"","description":"","filename":"6.SupplementaryTable2.BEresultsoffastinggroup.docx","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/b300c609e6e9dbd8b6181f10.docx"},{"id":94472084,"identity":"9885a802-fe27-46b2-849d-b081cfe2f39e","added_by":"auto","created_at":"2025-10-27 15:40:42","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":18682,"visible":true,"origin":"","legend":"","description":"","filename":"7.SupplementaryTable3.BEresultsoffedgroup.docx","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/3a7223689c6771cc13bd573b.docx"},{"id":94472073,"identity":"40ee5a10-b6a6-4383-97dc-708868fd242f","added_by":"auto","created_at":"2025-10-27 15:40:40","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":157605,"visible":true,"origin":"","legend":"","description":"","filename":"4.SupplementaryFigure1.Literatureanalysis.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7748740/v1/b3ee440a80588c9f13d8e690.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"To investigate the effect of a high-fat diet on pharmacokinetics/renal function/RAAS-related parameters after a single dose of empagliflozin in healthy Chinese adults","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSodium-glucose transporter 2 (SGLT2) inhibitors (SGLT2i) are a class of oral hypoglycaemic agents initially approved by the United States Food and Drug Administration for use in patients with type 2 diabetes mellitus (T2DM) \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Currently, several SGLT2i have been approved for clinical use, including dagliflozin, cagliflozin, and empagliflozin (EMPA) \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. They can exert a direct blood glucose (blood-GLU) lowering effect by inhibiting renal SGLT2, and thus inhibiting glucose reabsorption in the kidneys; and this effect is not dependent on insulin \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. EMPA is the representative drug for SGLT2i and used mainly in the 10 mg and 25 mg dosage forms clinically \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe transit and absorption of drugs in the gastrointestinal tract may differ depending on food intake or fasting. Food consumption produces different physiological changes such as fluctuations in gastric and intestinal pH, delayed gastric emptying, increased bile secretion, and visceral blood flow \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. The physiological changes induced by a modified diet can influence the efficacy of several drugs, mainly by affecting pharmacokinetic (PK) mechanisms \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Managing drug-food interactions is essential for optimizing the PK parameters, safety profile, and effectiveness of EMPA.\u003c/p\u003e\u003cp\u003eA literature analysis showed that PK studies of a single dose of EMPA administration in the postprandial versus fasting state in healthy subjects were currently available in a total of six studies, three of which were conducted with 25 mg, two with 10 mg, and one with 50 mg separately \u003csup\u003e[\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Due to differences in dosage and experimental protocols, the main parameters of PK \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e, including maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e), time to reach C\u003csub\u003emax\u003c/sub\u003e (T\u003csub\u003emax\u003c/sub\u003e), and area under time-concentration curve (AUC) of the above studies, exhibited distinct characteristics. Two PK studies of 10 mg EMPA in different countries involving healthy participants showed opposite trends in PK parameters after fasting and consumption of a high-fat diet (HFD) \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Based on the above literature analysis, we first studied the effect of an HFD on the PK parameters of 10 mg EMPA in healthy Chinese adults.\u003c/p\u003e\u003cp\u003eIn addition to lowering blood-GLU levels, EMPA improves renal outcomes in patients with chronic kidney disease (CKD), including those with diabetic kidney disease (DKD) and non-DKD. Several studies have explored renal function-related pharmacodynamic (PD) parameters of EMPA, including blood urea nitrogen (BUN) and serum creatinine (SCr) \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. On the other hand, in addition to controlling blood-GLU and blood pressure, blocking the RAAS has been an important intervention for retarding DKD progression for decades \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. A new aldosterone synthase inhibitor, used with EMPA, has been reported to not only reduce albuminuria, but also have additional efficacy in the treatment of CKD \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eUsing the 10 mg EMPA bioequivalence (BE) study, we studied how HFD affected the PK parameters of EMPA and renal function-related PD and RAAS-related parameters after taking EMPA. Renal function-related parameters included blood-GLU, blood uric acid (blood-UA), BUN, SCr, urine glucose (urine-GLU), urine uric acid (urine-UA), urine α1-microglobulin (α1-MG), and urine β2-microglobulin (β2-MG), and RAAS-related parameters included blood renin concentration (PRC), angiotensin II (Ang II), and aldosterone (ALD).\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eLiterature analysis\u003c/h2\u003e\u003cp\u003eBased on Pubmed, Scoups, Wanfang and CNKI database, the literatures about PK research of EMPA were summarized. The analysis focused on the influence of a HFD on the main PK parameters: C\u003csub\u003emax\u003c/sub\u003e, T\u003csub\u003emax\u003c/sub\u003e and AUC.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eIn this study, the influence of HFD on PK/PD/RAAS parameters after EMPA administration was based on a BE study (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cde.org.cn\u003c/span\u003e\u003cspan address=\"https://www.cde.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Registration No. CTR20232603) in a randomized, open-label, two-period, two-sequence, two-way crossover study under fasting and fed conditions. The BE of two EMPAs was assessed: a generic 10 mg EMPA was as test (EMPA-T) (Sponsor information was not allowed to be displayed under the study agreement), and 10 mg branded Jardiance\u0026reg;, manufactured by the producer Boehringer Ingelheim (Ingelheim, Germany, Batchnumber, 1705039), was as a reference (EMPA-R).\u003c/p\u003e\u003cp\u003eAll trial-related procedures were performed at the Phase I Clinical Trial Research Center of the Drug Clinical Trial Institution of the Shanxi Provincial People\u0026rsquo;s Hospital. The study protocol was approved by the Ethics Committee of Shanxi Provincial People\u0026rsquo;s Hospital and approval Number 2023-045 for the PK study in the BE trial, 2023\u0026thinsp;\u0026minus;\u0026thinsp;364 and 2023\u0026thinsp;\u0026minus;\u0026thinsp;399 for the PD/RAAS study under fasting and fed conditions, respectively). This study was registered in Chinadrugtrials.org.cn (ChiCTR2400089102).\u003c/p\u003e\n\u003ch3\u003eSubjects\u003c/h3\u003e\n\u003cp\u003eThe subjects in the BE/PK and PD/RAAS study were healthy Chinese volunteers. Before starting the study, medical and laboratory tests were conducted to ensure the health of volunteers. Smokers, heavy drinkers, those who used drugs that affected kidney metabolism within the previous 4 weeks, those who had taken any medicine within the previous 7 days, those who had a history of medication allergies, hypoglycemia or hypotension, those who had participated in previous clinical studies within the previous three months, and those with any significant clinical abnormality were excluded. In accordance with the trial protocol, 30 volunteers were recruited for the study in the fasting group and 30 in the fed group.\u003c/p\u003e\n\u003ch3\u003eEmpagliflozin administration\u003c/h3\u003e\n\u003cp\u003eThe day before the study, the participants were asked to avoid eating particular fruits (such as dragon fruit, mango, and grapefruit) and xanthine-rich foods, thus avoiding excessive physical exercise. The participants consumed a uniformly prepared dinner and stopped eating at 10:00 AM.\u003c/p\u003e\u003cp\u003eOn the day of the study, the subjects in the fasting group were administered one tablet of EMPA with 240 mL of water at 8:00 AM (study time point: 0 h). The fed group was fed a standard HFD 30 min before EMPA administration (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The component list of HFD is shown in Supplementary Table\u0026nbsp;1. Taking subject 1 as an example, he started his first bite at 7:30 AM and completed all meals within 29 min. At 8:00 AM, subject 1 took one tablet of EMPA with 240 mL water. Subsequent subjects, according to their number, at 1-min intervals, started their HFD and took EMPA. No food was allowed for 4 h after the dose, and in addition to ambulation, everyone was in a sitting position. Water (200 mL) was uniformly available for 2 h after the administration.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eBlood samples of BE/PK measurements\u003c/h3\u003e\n\u003cp\u003eVenous blood samples (3 mL per sample) were obtained before administering the medication (0 h) and at 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 4, 6, 8, 10, 12, 24, 36, and 48 h after EMPA administration under both fasting and fed conditions. Samples were centrifuged at 2,500 \u0026times; g for 10 min, and the serum was extracted and frozen at -60℃ for 60 min. Plasma concentrations of EMPA were detected using LC-MS/MS.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eBlood samples of PD/RAAS measurements\u003c/h2\u003e\u003cp\u003eBlood samples were collected three times to measure the PD and RAAS-related indicators. The first time in the fasting group was completed from 7:30 AM to 7:50 AM on the day of the study (i.e., before EMPA administration). In the fed group, the first collection time was from 7:00 AM to 7:20 AM, that is, before the HFD and EMPA administration. The second and the third time was after 2 h and 4 h of taking EMPA, respectively (time points: 2 h and 4 h). All blood samples were centrifuged at 3,800 rpm at 4\u0026deg;C for 8 min. The protocol is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eBlood GLU levels were measured using a Beckman Coulter AU5800 fully automatic biochemical analyzer (Beckman Coulter International Trading Co., LTD, USA). Insulin levels were analyzed using chemiluminescent immunoassay (Roche Cobase 601; Roche Diagnostics GmbH, Germany). Renal function-related indicators, including BUN, SCr, and blood UA and RAAS-related indices, including PRC, Ang II, and ALD, were measured using AutoLumo A2000 Plus (Zhengzhou Antu Biological Engineering Co. LTD, China). eGFR was determined using the following formula \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"469\" height=\"65\"\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eUrine samples of PD measurements\u003c/h3\u003e\n\u003cp\u003eUrine samples were collected twice. The first time was after waking up at 6:00 AM and before 8:00 AM on the study day (study period: -2\u0026thinsp;~\u0026thinsp;0 h). The second administration was within 4 h of EMPA administration (study period, 0\u0026thinsp;~\u0026thinsp;4 h). Urine from each subject was collected separately on his own in a clean 1,000 mL cylinder. Urine samples (8 mL) were tested for urine-GLU and urine-UA using a Beckman Coulter AU5800 fully automatic biochemical analyzer (Beckman Coulter International Trading Co., LTD, USA). Urine samples (8 mL) were centrifuged at 1,500 rpm at room temperature for 5 min, and the levels of urine α1-MG and β2-MG were measured using an automatic specific protein analyzer, BIOSYSTEM BA400 (Biosystems S.A. Costa Barcelona, Spain).\u003c/p\u003e\n\u003ch3\u003eSafety observation\u003c/h3\u003e\n\u003cp\u003ePotential adverse events (AEs) and vital signs (systolic and diastolic blood pressure, body temperature, and pulse rate) were assessed throughout the study. AEs were described according to the \u0026ldquo;Common Terminology Criteria for Adverse Events (version 2025\u0026rdquo;). Researchers recorded AEs in terms of their seriousness, intensity, time course, outcome, and relationship with the study drug.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003ePK parameters included C\u003csub\u003emax\u003c/sub\u003e, T\u003csub\u003emax\u003c/sub\u003e, and area under the time-concentration curve from administration to the last observed concentration at time t (AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e). area under the time-concentration curve extrapolated to infinity (AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e). percentage of the residual area of the AUC (AUC\u003csub\u003e_%Extrap\u003c/sub\u003e), terminal half-life (t\u003csub\u003e1/2\u003c/sub\u003e), and elimination rate constant (λ\u003csub\u003ez\u003c/sub\u003e). The PK study employed a non-compartmental method using Statistical Analysis System (SAS) version 9.4. Blood concentration-time data were collected after fasting or fed administration. The PK parameters were statistically analyzed. The AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e for EMPA was calculated using the trapezoidal method. If the 90% CI for the GMR of AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e, AUC\u003csub\u003e0~\u0026infin;\u003c/sub\u003e, and C\u003csub\u003emax\u003c/sub\u003e fell within the statistical range of 80.00% to 125.00% as proposed by the NMPA, then the fasting and fed conditions are considered bioequivalent \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe PD/RAAS statistical analysis was performed using SPSS 22.0. Due to the small sample size (n\u0026thinsp;\u0026lt;\u0026thinsp;30), the Shapiro-Wilk test was used to analyze all variables for normal distribution. Data that conformed to the normal distribution were analyzed using the Mann-Whitney U test, while data that did not conform were analyzed using the independent rank sum test. All continuous variable data are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. All reported P values were two-tailed, and statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eLiterature analysis\u003c/h2\u003e\u003cp\u003eSupplementary Fig.\u0026nbsp;1 shows that the five PK studies, including 25 mg EMPA and 10 mg EMPA, were based on the BE study, and the other 50 mg study was based on the original EMPA data.\u003c/p\u003e\u003cp\u003eTo analyze whether HFD had effects of HFD on the PK parameters, we compared four studies in which EMPA was performed using warm water. The results of three studies showed that HFD decreased both C\u003csub\u003emax\u003c/sub\u003e and AUC, which were conducted at doses of 10, 25, and 50 mg, whereas another study on 10 mg showed the opposite result, that is, HFD increased both C\u003csub\u003emax\u003c/sub\u003e and AUC of EMPA.\u003c/p\u003e\u003cp\u003eIn these two studies on 10 mg EMPA, one showed that Jordanian participants had an increase in the mean C\u003csub\u003emax\u003c/sub\u003e and AUC of approximately 50% to 74% after consuming HFD, and another showed that the average C\u003csub\u003emax\u003c/sub\u003e of Chinese volunteers dropped to 80.8% after consuming HFD.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eThe participants included in the analysis\u003c/h2\u003e\u003cp\u003eOf the 30 volunteers enrolled in the fasting group, one subject withdrew due to syncope before the first period of administration, and the other two subjects withdrew at the second period. In the HFD group, one voluntarily withdrew after the end of the first period and one did not complete HFD at the second period.\u003c/p\u003e\u003cp\u003eAccording to the sensitivity analysis, the plasma concentrations of the participants included in the PK parameter set and the BE set for analysis were as follows: EMPA-R (n\u0026thinsp;=\u0026thinsp;28) and EMPA-T (n\u0026thinsp;=\u0026thinsp;28) in the fasting group and EMPA-R (n\u0026thinsp;=\u0026thinsp;29) and EMPA-T (n\u0026thinsp;=\u0026thinsp;29) in the fed group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eParticipants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSituations of the participants\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFasting group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFed group\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThe enrolled participants\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThe participants\u003c/p\u003e\u003cp\u003ewho withdrew or dropped out\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEMPA-T and EMPA-R: n\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003cp\u003eEMPA-T: n\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003cp\u003eEMPA-R: n\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEMPA-T: n\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003cp\u003eEMPA-R: n\u0026thinsp;=\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThe participants\u003c/p\u003e\u003cp\u003ewho included in the analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEMPA-R: n\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e\u003cp\u003eEMPA-T: n\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEMPA-R: n\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e\u003cp\u003eEMPA-T: n\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eNotes: EMPA-R, a branded empagliflozin was as the reference. EMPA-T, a generic empagliflozin was the test.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOur research confirmed that the 90% CI for the GMR of AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e, AUC\u003csub\u003e0~\u0026infin;\u003c/sub\u003e, and C\u003csub\u003emax\u003c/sub\u003e was within the statistical range of 80.00%~125.00% when 10 mg EMPA-T was compared to EMPA-R under fasting (Supplementary Table\u0026nbsp;2) and fed conditions (Supplementary Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eIn the study of the effect of HFD on PK parameters, the plasma concentrations included in the analysis were as follows: fasting group (n\u0026thinsp;=\u0026thinsp;56, EMPA-R (n\u0026thinsp;=\u0026thinsp;28) and EMPA-T (n\u0026thinsp;=\u0026thinsp;28)) and fed group (n\u0026thinsp;=\u0026thinsp;58: EMPA-R (n\u0026thinsp;=\u0026thinsp;29) and EMPA-T (n\u0026thinsp;=\u0026thinsp;29)) according to the sensitivity analysis. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e lists these details.\u003c/p\u003e\u003cp\u003e In the PD/RAAS study, 42 healthy subjects signed an informed consent form (fasting, n\u0026thinsp;=\u0026thinsp;19; fed, n\u0026thinsp;=\u0026thinsp;23) and completed the entire study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eThe influence of HFD on plasma concentrations\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows plasma concentrations at 20 blood sampling points before and 48 h after EMPA administration. A total of 18 time points had higher concentrations in the fasting than in the fed from 0.25 h to 36 h, with 16 points significantly different, clustered between 0.25 h and 12 h (all: P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). At 0.25 h after dosing, the plasma concentration ratio of fasting to fed was highest at 3.3-fold, followed by 3.0-fold at 0.5 h and 2.3-fold at 1 h.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparisons of plasma concentrations\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSerial number\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eTime points of sampling (h)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e\u003cp\u003ePlasma concentrations\u003c/p\u003e\u003cp\u003e(ng/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003eCV of the\u003c/p\u003e\u003cp\u003eplasma concentrations (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFasting (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFed (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFasting/fed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFasting (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFed (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBQL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBQL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;31.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e118.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e162.73\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e102.6\u0026thinsp;\u0026plusmn;\u0026thinsp;61.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;31.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e59.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e90.61\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e165.7\u0026thinsp;\u0026plusmn;\u0026thinsp;60.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;49.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e36.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e67.83\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e167.5\u0026thinsp;\u0026plusmn;\u0026thinsp;44.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e87.4\u0026thinsp;\u0026plusmn;\u0026thinsp;39.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e26.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e44.90\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e163.2\u0026thinsp;\u0026plusmn;\u0026thinsp;35.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.7\u0026thinsp;\u0026plusmn;\u0026thinsp;33.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e21.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e35.25\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e157.9\u0026thinsp;\u0026plusmn;\u0026thinsp;32.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.1\u0026thinsp;\u0026plusmn;\u0026thinsp;28.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e20.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e29.86\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e151.8\u0026thinsp;\u0026plusmn;\u0026thinsp;27.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.2\u0026thinsp;\u0026plusmn;\u0026thinsp;26.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e18.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e27.88\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e148.2\u0026thinsp;\u0026plusmn;\u0026thinsp;28.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e91.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e19.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e24.71\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e138.0\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e22.05\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e130.5\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.04\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123.3\u0026thinsp;\u0026plusmn;\u0026thinsp;17.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e79.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18.86\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e74.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e14.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e16.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18.77\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e20.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20.60\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e21.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.281\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e29.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.483\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e39.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e35.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.839\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e40.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e34.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eNotes: \u003csup\u003e*\u003c/sup\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.01, plasma concentration of the fasting \u003cem\u003evs\u003c/em\u003e the fed. \u003csup\u003e#\u003c/sup\u003eCV of the fed was higher than that of the fasting. CV, coefficient of variation.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparisons of plasma concentrations Notes: \u003csup\u003e*\u003c/sup\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.01, plasma concentration of the fasting \u003cem\u003evs\u003c/em\u003e the fed. \u003csup\u003e#\u003c/sup\u003eCV of the fed was higher than that of the fasting. CV, coefficient of variation.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSerial number\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eTime points of sampling (h)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e\u003cp\u003ePlasma concentrations\u003c/p\u003e\u003cp\u003e(ng/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003eCV of the\u003c/p\u003e\u003cp\u003eplasma concentrations (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFasting (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFed (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFasting/fed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFasting (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFed (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBQL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBQL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;31.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e118.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e162.73\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e102.6\u0026thinsp;\u0026plusmn;\u0026thinsp;61.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;31.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e59.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e90.61\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e165.7\u0026thinsp;\u0026plusmn;\u0026thinsp;60.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;49.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e36.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e67.83\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e167.5\u0026thinsp;\u0026plusmn;\u0026thinsp;44.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e87.4\u0026thinsp;\u0026plusmn;\u0026thinsp;39.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e26.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e44.90\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e163.2\u0026thinsp;\u0026plusmn;\u0026thinsp;35.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.7\u0026thinsp;\u0026plusmn;\u0026thinsp;33.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e21.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e35.25\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e157.9\u0026thinsp;\u0026plusmn;\u0026thinsp;32.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.1\u0026thinsp;\u0026plusmn;\u0026thinsp;28.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e20.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e29.86\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e151.8\u0026thinsp;\u0026plusmn;\u0026thinsp;27.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.2\u0026thinsp;\u0026plusmn;\u0026thinsp;26.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e18.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e27.88\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e148.2\u0026thinsp;\u0026plusmn;\u0026thinsp;28.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e91.5\u0026thinsp;\u0026plusmn;\u0026thinsp;22.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e19.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e24.71\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e138.0\u0026thinsp;\u0026plusmn;\u0026thinsp;21.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e22.05\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e130.5\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.04\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123.3\u0026thinsp;\u0026plusmn;\u0026thinsp;17.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e79.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18.86\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e74.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e14.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.0\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e16.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18.77\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e20.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20.60\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.004\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e21.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.281\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e29.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.483\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e39.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e35.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.839\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e40.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e34.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWithin 3 h after administration, the plasma concentration variability in the fed group, expressed as the coefficient of variation (CV), was higher than that in the fasting group, suggesting that the HFD may affect the absorption of EMPA among individuals \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eThe influence of HFD on PK parameters\u003c/h2\u003e\u003cp\u003eThe calculated PK parameters, including T\u003csub\u003emax\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e, AUC\u003csub\u003e0~\u0026infin;\u003c/sub\u003e, AUC\u003csub\u003e_%Extrap\u003c/sub\u003e, t\u003csub\u003e1/2\u003c/sub\u003e and λ\u003csub\u003ez\u003c/sub\u003e are presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparisons of pharmacokinetic parameters Notes: C\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration. T\u003csub\u003emax\u003c/sub\u003e, time to reach C\u003csub\u003emax\u003c/sub\u003e. AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e, area under time-concentration curve from administration to last observed concentration at time t. AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e, area under time-concentration curve from administration extrapolated to infinity. AUC_\u003csub\u003e%Extrap\u003c/sub\u003e, percentage of residual area of AUC. t\u003csub\u003e1/2\u003c/sub\u003e, terminal half-life. λ\u003csub\u003ez\u003c/sub\u003e, elimination rate constant. CI, confidence interval.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eUnits\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eGeometric mean and ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e90%CI of the ratio (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFasting\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFasting/Fed (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e78.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e49.05\u0026thinsp;~\u0026thinsp;107.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e186.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e112.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e165.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e152.29\u0026thinsp;~\u0026thinsp;178.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eng\u0026middot;h/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1305.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e950.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e137.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e127.21\u0026thinsp;~\u0026thinsp;147.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eng\u0026middot;h/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1331.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e977.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e136.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e125.86\u0026thinsp;~\u0026thinsp;146.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC_%\u003csub\u003eExtrap\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e70.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e44.06\u0026thinsp;~\u0026thinsp;96.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003et\u003csub\u003e1/2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e98.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e85.81\u0026thinsp;~\u0026thinsp;110.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eλ\u003csub\u003ez\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e100.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e96.41\u0026thinsp;~\u0026thinsp;107.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparisons of pharmacokinetic parameters\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eUnits\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eGeometric mean and ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e90%CI of the ratio (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFasting\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eFasting/Fed (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e78.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e49.05\u0026thinsp;~\u0026thinsp;107.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e186.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e112.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e165.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e152.29\u0026thinsp;~\u0026thinsp;178.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eng\u0026middot;h/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1305.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e950.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e137.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e127.21\u0026thinsp;~\u0026thinsp;147.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eng\u0026middot;h/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1331.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e977.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e136.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e125.86\u0026thinsp;~\u0026thinsp;146.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAUC_%\u003csub\u003eExtrap\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e70.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e44.06\u0026thinsp;~\u0026thinsp;96.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003et\u003csub\u003e1/2\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e8.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e98.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e85.81\u0026thinsp;~\u0026thinsp;110.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eλ\u003csub\u003ez\u003c/sub\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/hr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e100.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e96.41\u0026thinsp;~\u0026thinsp;107.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eNotes: C\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration. T\u003csub\u003emax\u003c/sub\u003e, time to reach C\u003csub\u003emax\u003c/sub\u003e. AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e, area under time-concentration curve from administration to last observed concentration at time t. AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e, area under time-concentration curve from administration extrapolated to infinity. AUC_\u003csub\u003e%Extrap\u003c/sub\u003e, percentage of residual area of AUC. t\u003csub\u003e1/2\u003c/sub\u003e, terminal half-life. λ\u003csub\u003ez\u003c/sub\u003e, elimination rate constant. CI, confidence interval.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe GMR for T\u003csub\u003emax\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e, AUC\u003csub\u003e0~\u0026infin;\u003c/sub\u003e and AUC\u003csub\u003e_%Extrap\u003c/sub\u003e between the fasting and the fed were 78.44%, 165.53%, 137.25%, 136.16% and 70.04%, respectively, and their corresponding 90% CI were (49.05\u0026thinsp;~\u0026thinsp;107.46)%, (152.29\u0026thinsp;~\u0026thinsp;178.77)%, (127.21\u0026thinsp;~\u0026thinsp;147.29)%, (125.86\u0026thinsp;~\u0026thinsp;146.45)% and (44.06\u0026thinsp;~\u0026thinsp;96.16)%, respectively, which were not within the bioequivalent range (80.00\u0026thinsp;~\u0026thinsp;125.00)% \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, suggesting that HFD delayed T\u003csub\u003emax\u003c/sub\u003e and decreased C\u003csub\u003emax\u003c/sub\u003e and AUC of 10 mg EMPA.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eThe influence of HFD on PD parameters\u003c/h2\u003e\u003cp\u003eThe results for urine-GLU, urine-UA, insulin, blood-GLU, and blood-UA levels are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026thinsp;~\u0026thinsp;2E.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, the urine-GLU levels in the fasting and fed groups within 4 h of EMPA administration were significantly higher than those before administration (two: P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Additionally, within 4 h after EMPA administration, the fed group exhibited a significantly higher urine GLU level than the fasting group (P\u0026thinsp;=\u0026thinsp;0.024).\u003c/p\u003e\u003cp\u003eFrom Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD, we can see that after 2 h and 4 h of EMPA administration in the fasting group, the fasting blood-GLU and insulin levels were significantly decreased (four: P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, the decreased fasting blood-GLU and insulin levels were still within normal ranges.\u003c/p\u003e\u003cp\u003eFrom Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, it can also be seen that after EMPA administration, the trend of blood-UA decreased with an increase in urine-UA excretion, which only showed a significant difference in the fed group (two: P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eThe results for SCr, BUN, and eGFR are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF\u0026thinsp;~\u0026thinsp;2H. In the fed group, 2 h and 4 h after taking EMPA, compared with before taking EMPA, there were significant differences on the SCr, BUN, and eGFR levels (six: P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In the fasting group, there was a significant difference in BUN between 2 and 4 h after administration of EMPA alone for BUN compared to before taking the medicine (two: P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). After the administration of EMPA in the fasting and fed groups, the above three indicators were also within the normal range.\u003c/p\u003e\u003cp\u003eThe results for the two urinary microglobulins α1-MG and β2-MG are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eI and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eJ. In the fasting group, both urinary α1-MG and β2-MG levels significantly decreased after EMPA administration compared to those before EMPA administration (P\u0026thinsp;=\u0026thinsp;0.005 and P\u0026thinsp;=\u0026thinsp;0.017, respectively). In the fed group, the EMPA intervention significantly reduced urinary β2-MG levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), which exceeded the normal range.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eThe influence of HFD on RAAS-related parameters\u003c/h2\u003e\u003cp\u003eThe levels of PRC and Ang II in the fasting group were significantly higher than those before EMPA administration when EMPA was administered for 2 and 4 h (four: P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and the increased PRC levels were higher than the upper limit of normal. However, there was no significant change in ALD levels.\u003c/p\u003e\u003cp\u003eCompared with before EMPA administration, PRC, Ang II, and ALD showed a downward trend in the fed group 4 h after EMPA administration, and there were significant differences in PRC and Ang II (four: P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The results are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eSafety observation\u003c/h2\u003e\u003cp\u003eThe AEs observed in this study are listed in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The overall incidence of AEs in the fasting and fed groups was 14.3% and 13.8%, respectively. There were no significant differences between the two incidence rates.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAdverse events\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDescriptions\u003c/p\u003e\u003cp\u003eof adverse events\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFasting (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eFed (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumbers\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTime of occurrence\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNumbers\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTime of occurrence\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDecreased diastolic blood pressure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 h\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDizziness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDecreased fasting blood glucose\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrinary tract infection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertriglyceridemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIncreased serum creatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated low-density lipoprotein cholesterol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated alanine aminotransferase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated γ-glutamyltranspeptidase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48 h\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eNotes: \u003csup\u003e*\u003c/sup\u003e All descriptions of adverse events were according to \u0026ldquo;Common Terminology Criteria for Adverse Events (version 2025)\u0026rdquo;, with a severity of \u0026ldquo;Grade 1\u0026rdquo;, and all outcomes were \u0026ldquo;recovered\u0026rdquo;. \u003csup\u003e#\u003c/sup\u003e The time after taking empagliflozin.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe most reported AE in both groups was urinary tract infection, with 2 cases in each group. The AEs observed in both groups included decreased diastolic blood pressure, hypertriglyceridemia, and elevated low-density lipoprotein cholesterol levels. AEs reported only in the fasting group included dizziness, nausea, and elevated serum creatinine level. AEs that occurred only in the fed group included elevated alanine aminotransferase and γ-glutamyl transpeptidase levels.\u003c/p\u003e\u003cp\u003eAll of the above AEs were described in the instructions for Jardiance\u0026reg; and were Grade 1 in severity, recovered spontaneously without any intervention, and no subject withdrew from the trial due to AEs.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eLifestyle, including exercise and diet, can alter several physiological functions of the human body. Food intake can cause various physiological changes in the human gastrointestinal tract, such as changes in the gastrointestinal pH, gastric emptying time, and metabolic enzymes \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. These changes can affect the PK characteristics of certain drugs by altering their release, absorption, distribution, metabolism, and/or excretion \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. PK and PD interactions with food can lead to reduced drug efficacies. This is known as the negative food effect, which refers to a reduction in bioavailability when a drug is ingested \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAccording to the most previous studies, administering EMPA after HFD resulted in decreases in mean C\u003csub\u003emax\u003c/sub\u003e and AUC, \u003csup\u003e[\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e but there were also individual studies that yielded opposite results \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. The HFD used in the aforementioned studies refers to foods with a total calorie intake of (800\u0026thinsp;~\u0026thinsp;1000) kcal, and calories from fat should provide (500\u0026thinsp;~\u0026thinsp;600) kcal \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. It has been confirmed that HFDs have more significant physiological impacts on the gastrointestinal tract, therefore regulatory authorities recommend using high calorie and high-fat meals in food impact studies \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e Our study indicated that the HFD used in this study, which provided 934.74 kcal, delayed T\u003csub\u003emax\u003c/sub\u003e after EMPA administration while reducing C\u003csub\u003emax\u003c/sub\u003e and AUC, including AUC\u003csub\u003e0\u0026thinsp;~\u0026thinsp;t\u003c/sub\u003e and AUC\u003csub\u003e0~\u0026infin;\u003c/sub\u003e.\u003c/p\u003e\u003cp\u003eIn healthy subjects, PD drug-drug interactions between EMPA and other hypoglycemic medicines such as evogliptin \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e, metformin and lobeglitazone \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e were explored based on the PK properties of EMPA. The effect of food on PK parameters often begins in phase I clinical trials, based on observations in healthy subjects \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e. With increasing clinical evidence of EMPA in patients with non-DKD, \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e focusing on the direct effect of EMPA on renal function-related indicators in healthy people may lay a foundation for further exploration of its improvement in patients with CKD.\u003c/p\u003e\u003cp\u003eAmong the indicators related to kidney function, the first indicator we focused on was the blood-UA level. In a double-blind, randomized, placebo-controlled study, 45 healthy volunteers underwent blood and urine sampling one month after EMPA administration. It was found that their blood-UA levels decreased by 28.4% \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Our results showed a si milar downward trend in blood-UA levels in the above study. Unlike the chronic effects described above, our research showed an acute effect of EMPA on decreasing blood-UA levels in both fasting and fed states. This decrease in blood-UA was associated with an increase in urine-UA \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003eand urine-GLU \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e levels, which was also observed in this study.\u003c/p\u003e\u003cp\u003eMore urine-UA and urine-GLU were excreted in the fed group, indicating that EMPA could dynamically regulate blood-GLU, urine-GLU, blood-UA, and urine-UA according to the different states of the body. Taking blood-GLU as an example, it appeared that there was a dynamic balance between the increase in blood-GLU due to HFD and the increase in urine-GLU excretion, which ultimately determined the extent of urine-GLU excretion. A similar balance between the increase in hepatic glucose production and the increase in urine-GLU excretion immediately after SGLT2 inhibition has been observed in a clinical study \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDecreasing effects of EMPA on α1-MG were observed in patients with acute decompensated heart failure and in \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, patients with renal proximal tubulopathy in the Fanconi-Bickel syndrome \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. Both α1-MG and β2-MG are regarded as markers of renal tubular impairment. Notably, patients with DKD have been found to exhibit higher levels of α1-MG than patients with T2DM \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Children with severe mycoplasma pneumoniae pneumonia-related acute kidney injury (AKI) had higher α1-MG and β2-MG levels than non-AKI children \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. Unlike the previous reports, the acute effects of EMPA on decreasing α1-MG and β2-MG levels were also observed in this study in healthy volunteers.\u003c/p\u003e\u003cp\u003eIt has been suggested that combining RAAS inhibitors and a low-protein diet might be a high-quality intervention to slow CKD progression \u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e. On the other hand, augmenting RAAS inhibitors with new drug classes, such as SGLT2 inhibitor, has the potential to improve clinical outcomes in a broad range of patients with CKD \u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. To study focused on the effect of EMPA on the RAAS axis in the dietary state. Our results suggest that taking EMPA on an empty stomach in healthy subjects increased the PRC level above the upper limit of normal but ultimately had little effect on the ALD level. If EMPA was administered after a meal, the three indicators on the RAAS axis remained within the normal range. This suggests that HFD plays a limited role.\u003c/p\u003e\u003cp\u003eThe hypoglycemic mechanism of EMPA is associated with increased urine-GLU excretion \u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. We observed that a significant reduction in blood-GLU in the fasting group led to a significant decrease in insulin levels at corresponding time points. This might prevent the induction of hypoglycemia \u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e and the safety of EMPA was confirmed by the blood-GLU test results within 4 h of taking EMPA under fasting and fed conditions, which was to maintain the reduced blood-GLU within the normal range without the risk of hypoglycaemia \u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn summary, based on the BE study, we discuss the effects of HFD on PK parameters, renal function-related PD parameters, and RAAS-related indicators affected by EMPA in healthy subjects. Our results suggest that although HFD significantly affected the PK parameters of EMPA, it did not affect renal function-related PD parameters and RAAS-related indicators of EMPA.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all the volunteers who participated in this study, Dr. Xiaocheng Wang for providing statistical guidance, and the Ethics Committee for their guidance and supervision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Yi Jin and Hui Liao; Data curation: Yi Jin and Lu Bai; Formal analysis: Yi Jin and Wenyan Zhao; Funding acquisition: Hui Liao; Investigation, Yi Jin, Wenyan Zhao, Hui Wu and Lu Bai; Methodology, Sunqi Ding and Hui Liao; Project administration: Hui Liao; Resources, Zhaodi Han and Hui Liao; Software, Qian Li and Shuangshuang Tian; Supervision, Hui Liao; Validation, Qian Li and Zhaodi Han; Visualization, Yi Jin and Hui Wu; Writing \u0026ndash; original draft: Wenyan Zhao,Sunqi Ding, Qian Li, Shuangshuang Tian and Hui Liao; Writing \u0026ndash; review and editing: Wenyan Zhao and Hui Liao.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Demonstration Project on Reformation and Quality Development of Public Hospitals (No.SCP-2023-8), the Local Science and Technology Development Funds Projects Guided by Central Government (No. YDZJSX2021C027), Basic Research Program of Shanxi Province (No.202103021224370).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSome datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Shanxi Provincial People\u0026rsquo;s Hospital (BE protocol code:\u0026nbsp;2023-045,\u0026nbsp;approval date: 27-7-2023,\u0026nbsp;PD protocol code: 2023-364 (fasting) and 2023-399 (fed), approval date:29-8-2023 (fasting) and 28-9-2023 (fed)).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all participants involved in the study. Written informed consent has been obtained from the participants to publish this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCunningham C, Jabri A, Alhuneafat L, Aneja A. A comprehensive guide to sodium glucose cotransport inhibitors. Curr Probl Cardiol. 2023;48:101817.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan der Aart-van, der Beek AB, de Boer RA, Heerspink HJL. Kidney and heart failure outcomes associated with sglt2 inhibitor use. Nat Rev Nephrol. 2022;18:294\u0026ndash;306.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eScheen AJ. Sodium\u0026ndash;glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. 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Adv Ther. 2024;41:2826\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"empagliflozin, high-fat diet, pharmacokinetics, renal function-related parameters, RAAS-related parameters","lastPublishedDoi":"10.21203/rs.3.rs-7748740/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7748740/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eLiterature showed that a high-fat diet (HFD) has an opposite effect on the pharmacokinetic (PK) parameters of empagliflozin (EMPA). EMPA combined with renin-angiotensin-aldosterone system(RAAS)inhibitors is widely used for the treatment of chronic kidney disease. In this study, we investigated the effects of HFD on the PK of EMPA, renal function-related parameters (RF-RP), and RAAS-related parameters (RAAS-RP) affected by EMPA.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eBased on a bioequivalence study in healthy Chinese adults, twenty blood concentration values were obtained before and within 48 h after EMPA administration in the fasting and fed groups. The maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e), time to reach C\u003csub\u003emax\u003c/sub\u003e (T\u003csub\u003emax\u003c/sub\u003e), and area under the time-concentration curve (AUC) were calculated. Guided by C\u003csub\u003emax\u003c/sub\u003e and T\u003csub\u003emax\u003c/sub\u003e, urine and blood samples were collected and glucose, uric acid, blood urea nitrogen, serum creatinine, insulin, urine α1-microglobulin, β2-microglobulin, plasma renin concentration (PRC), angiotensin II, and aldosterone levels were tested. Estimated glomerular filtration rates were calculated.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe 90% confidence intervals of the geometric mean ratios of fasting T\u003csub\u003emax\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, and AUC for the fed group were not within the bioequivalence range. After taking EMPA, urine glucose was higher but β2-microglobulin was significantly lower than before taking EMPA (four: P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in the two groups, and both indicators exceeded the normal ranges. Fasting administration of EMPA increased PRC (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) but had no effect on aldosterone levels. Other indicators before and after EMPA administration in both groups were within the normal ranges.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eHFD affected the PK parameters of EMPA; however, no further effects on RF-RP and RAAS-RP were by EMPA.\u003c/p\u003e\u003ch2\u003eClinical trial registration\u003c/h2\u003e\u003cp\u003eChiCTR2400089102, retrospectively registered in \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.chictr.org.cn/\u003c/span\u003e\u003cspan address=\"https://www.chictr.org.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e on 2 September 2024.\u003c/p\u003e","manuscriptTitle":"To investigate the effect of a high-fat diet on pharmacokinetics/renal function/RAAS-related parameters after a single dose of empagliflozin in healthy Chinese adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-27 14:19:24","doi":"10.21203/rs.3.rs-7748740/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-22T12:34:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-03T01:32:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-02T05:31:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-21T00:54:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79145448785442160679317845012549801923","date":"2025-11-13T01:04:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"108203571759359717195716080905302752825","date":"2025-11-11T14:43:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279967137092185858168979944064687602916","date":"2025-10-20T06:54:36+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-13T14:41:57+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-07T21:31:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-04T01:58:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-04T01:58:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pharmacology and Toxicology","date":"2025-09-30T07:49:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3585b980-1d7a-4e6f-a9aa-44a6d64cf00c","owner":[],"postedDate":"October 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T16:04:57+00:00","versionOfRecord":{"articleIdentity":"rs-7748740","link":"https://doi.org/10.1186/s40360-026-01099-y","journal":{"identity":"bmc-pharmacology-and-toxicology","isVorOnly":false,"title":"BMC Pharmacology and Toxicology"},"publishedOn":"2026-02-09 15:58:03","publishedOnDateReadable":"February 9th, 2026"},"versionCreatedAt":"2025-10-27 14:19:24","video":"","vorDoi":"10.1186/s40360-026-01099-y","vorDoiUrl":"https://doi.org/10.1186/s40360-026-01099-y","workflowStages":[]},"version":"v1","identity":"rs-7748740","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7748740","identity":"rs-7748740","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}