Randomized, Open-Label Pharmacokinetic Study of Oral Magnesium Oxide in Healthy Volunteers

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This study aimed to evaluate the safety, dose-dependent absorption, and pharmacokinetics of oral magnesium oxide at two dosage levels in healthy male volunteers. Methods A randomized, open-label pharmacokinetic study was conducted in 24 healthy male volunteers aged 18–45 years, who were equally assigned to receive a single oral dose of either 750 mg or 2000 mg of magnesium oxide. Plasma magnesium concentrations were measured at baseline and multiple time points up to 12 hours post-dose using colorimetric assay. Pharmacokinetic parameters including Cmax, Tmax, AUC, half-life, mean residence time, and clearance were calculated using non-compartmental analysis. Safety was assessed by monitoring vital signs, laboratory parameters, ECG, and adverse events. Results The study showed saturable, nonlinear absorption kinetics with no proportional increase in Cmax or AUC at the higher dose. Incremental exposure parameters were also comparable between doses, further reinforcing the presence of saturable and nonlinear absorption kinetics. Tmax was significantly shorter in the 2000 mg group (p = 0.025). Both doses were well tolerated without serious adverse events or gastrointestinal side effects. Conclusion: In summary, this study demonstrates that oral MgO displays rate differences without proportional exposure gains across 750–2000 mg, supporting a saturable absorption model with a practical ceiling on systemic delivery. These findings provide a pharmacokinetic rationale for cautious dose escalation and support the feasibility of MgO as a well-tolerated oral option for perioperative magnesium optimization. Magnesium Oxide Oral Administration Pharmacokinetics Safety Drug Tolerance Figures Figure 1 Figure 2 Figure 3 Introduction Magnesium is the second most abundant intracellular cation and serves as an essential cofactor for over 300 enzymatic reactions regulating diverse physiological processes[ 1 ]. Maintaining adequate magnesium levels is crucial for normal cellular and systemic function [ 2 ]. Hypomagnesemia is highly prevalent, affecting 10–30% of the general population and up to 60% of critically ill patients[ 3 ].This deficiency is significantly associated with increased postoperative pain, cardiac arrhythmias, and prolonged recovery, underscoring magnesium’s vital role in perioperative care[ 4 ]. Consequently, magnesium administration, valued for its analgesic, neuroprotective, and antiarrhythmic properties through mechanisms like antagonism of N-methyl-D-aspartate (NMDA) receptors, has become integral to Enhanced Recovery After Surgery (ERAS) protocols.[ 5 ] Magnesium oxide (MgO) is widely used for magnesium supplementation due to its high elemental content and affordability. However, MgO exhibits inherently low aqueous solubility, resulting in a low systemic bioavailability, typically estimated between 4–10%. Despite its clinical importance, comprehensive data characterizing the pharmacokinetics (PK) and dose proportionality of oral MgO are sparse and inconsistent[ 6 ]. The poor solubility requires gastric acid for conversion into absorbable magnesium ions, which complicates absorption kinetics, and previous studies have lacked the detailed characterization needed to optimize dosing regimens[ 7 ]. This study was designed to rigorously evaluate the safety and single-dose pharmacokinetic profiles of oral magnesium oxide at two distinct dosage levels: 750 mg and 2000 mg in healthy male volunteers. The primary objective was to fully characterize key PK parameters, including peak plasma concentration (Cmax), time to peak concentration (T max), and area under the concentration-time curve (AUC), to determine if systemic exposure increases proportionally with the dose. We specifically hypothesized that the intestinal absorption of MgO would exhibit non-linear, saturable kinetics driven by the limited capacity of transcellular transport pathways.[ 8 ] Methodology Study Design This was a randomized, open-label pharmacokinetic study conducted at the Clinical Trial and Research Unit, SRM Medical College Hospital and Research Centre. The study adhered to the principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice (ICH-GCP) [9]. Ethical approval was obtained from the Institutional Ethics Committee (Approval No. ECR8958INSTTN2013RR-19), and the study was registered prospectively with the Clinical Trials Registry - India (CTRI/2025/02/081449). All participants provided written informed consent before enrolment. Study Population Twenty-four healthy male volunteers aged 18-45 years, weighing at least 50 kg, were recruited. Eligibility criteria included normal clinical evaluation and laboratory tests, no history of smoking or alcohol intake, and no use of medication or supplements that could influence magnesium pharmacokinetics for at least 14 days prior to enrolment. Exclusion criteria encompassed systemic disorders (diabetes mellitus, hypertension, tuberculosis), clinically significant abnormalities in hepatic, renal, cardiac, gastrointestinal, neurological, endocrine, respiratory, metabolic, psychiatric, or haematological function, recent surgery, substance abuse, known hypersensitivity to magnesium compounds, participation in other clinical trials within 3 months, and significant blood donation or loss within the preceding three months. Randomization Participants were randomized using a simple randomization method into two equal groups (n=12 each) to receive a single oral dose of either 750 mg or 2000 mg of magnesium oxide Procedure Volunteers fasted overnight for at least 8 hours before dosing to minimize dietary confounding on magnesium absorption. On the study day, participants received the assigned magnesium oxide dose orally with 200 mL of water in a seated position under continuous medical supervision. Standard meals were provided after one-hour post-dose . ( Participant recruitment and flow through the study are shown in Figure 1) Sample Collection and Processing Venous blood samples (2 mL) were collected at baseline (pre-dose, T=0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4-, 6-, 8-, and 12-hours post-dose via an indwelling catheter. Blood was collected into heparinized tubes, centrifuged within 30 minutes to separate plasma, which was stored at 2-8°C and analyzed on the same day. Haemolyzed or lipemic samples were excluded from analysis. Assay Method Plasma magnesium concentrations were assessed using a validated colorimetric assay based on complex formation with xylidyl blue in an alkaline medium, measured by Beckman AU480/AU680 analyzers. Calcium interference was blocked by adding GEDTA. The assay exhibited linearity between 0.5 and 8 mg/dL, with between-day variation under 5% and accuracy better than 10%. Detection and quantification limits were 0.1 and 0.5 mg/dL, respectively. Calibration was performed weekly or with each lot change. Pharmacokinetic Analysis Pharmacokinetic parameters were calculated using PK Solutions 2.0 (Summit Research Services, Montrose, Colorado, USA). Primary parameters included peak plasma concentration (Cmax) and time to peak concentration (Tmax). The area under the plasma concentration-time curve was calculated from time zero to last measurable concentration (AUC_t) using the linear trapezoidal rule and extended to infinity (AUC_inf) by extrapolation using the elimination rate constant (kel), derived from the terminal log-linear slope. Elimination half-life (t_1/2) was calculated as 0.693/kel. Additional parameters included mean residence time (MRT) and apparent oral clearance (Cl/F). Inter-individual variability was expressed as coefficient of variation (CV). Statistical Analysis The data were assessed for normality using the Shapiro-Wilk test and confirmed for normality. The data which are normally distributed are summarized as mean ± standard deviation and for not normally distributed variables are summarized as median with interquartile range accordingly. Group comparisons for non-normally distributed data utilized the Mann-Whitney U test. Comparisons of each time point with baseline values were performed using a paired t-test. A sample size of 24 was calculated for a 80% power to detect, at a 5% significance level, and 1.15 as the effect size (Cohen’s d) [10]. Data analysis was performed using IBM Statistical Package for the Social Sciences (SPSS) software, version 26.0 (IBM Corp., Armonk, NY, USA). Safety Monitoring Vital signs were recorded throughout the study period. Laboratory safety evaluations included electrocardiography (ECG), renal and hepatic function tests, complete blood count, and serum electrolytes. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and abdominal discomfort were closely monitored. Any adverse events were documented. Participants received compensation consistent with ethical committee guidelines. Results Participant Characteristics A total of 24 healthy male volunteers were enrolled and randomized evenly into two groups receiving 750 mg (Group 1) or 2000 mg (Group 2) of oral magnesium oxide. All participants completed the study and provided evaluable pharmacokinetic data. Baseline demographic and clinical characteristics were comparable between groups with no statistically significant differences. ( Baseline demographics of the participants shown in Table 1 ). Table 1 Baseline demographic and clinical characteristics of the participants. Parameters Group1 (750 mg) Group 2 (2000 mg) P-value Age (years) 21.9 ± 1.1 23.2 ± 1.4 0.812 Height (cm) 170.4 ± 6.1 166.6 ± 8.7 0.342 Weight (kg) 63.6 ± 9.7 64.7 ± 11.1 0.789 BMI (kg/m²) 21.9 ± 2.4 23.2 ± 2.2 0.456 Data are presented as mean ± standard deviation. There were no statistically significant differences between the groups. In terms of the remaining baseline clinical characteristics, serum magnesium levels were comparable between Group 1 (750 mg) and Group 2 (2000 mg), with mean values of 1.95 ± 0.12 mg/dL and 1.97 ± 0.17 mg/dL, respectively (p = 0.891). Blood glucose levels were also similar across groups, with Group 1 showing 95.6 ± 7.6 mg/dL and Group 2 showing 87.8 ± 4.1 mg/dL (p = 0.134). There was no statistically significant difference in hemoglobin concentration, which measured 15.1 ± 1.3 g/dL in Group 1 and 15.6 ± 0.8 g/dL in Group 2 (p = 0.567). Similarly, red blood cell (RBC) counts (Group 1: 5.15 ± 0.39 ×10⁶/µL; Group 2: 5.30 ± 0.30 ×10⁶/µL) and white blood cell (WBC) counts (Group 1: 7511 ± 2203 cells/µL; Group 2: 6388 ± 1223 cells/µL) did not differ significantly between the groups (p = 0.623 and p = 0.289, respectively). Pharmacokinetic Parameters Non-compartmental analysis over the 0–12 h demonstrated non-dose-proportional systemic exposure of magnesium following oral magnesium oxide, consistent with saturable, non-linear absorption. Because magnesium is an endogenous analyte, both observed and baseline-corrected (incremental) analyses were performed using each subject’s pre-dose concentration at 0 h (C0). Non-Proportionality in Systemic Exposure Despite a 2.67-fold increase in the administered dose, the systemic delivery of magnesium did not increase proportionally. The key exposure parameters were similar across groups Cmax was not significantly different between the 750 mg and 2000 mg groups (p = 0.159). AUC0–12 was comparable between treatment arms (p = 0.573), indicating no meaningful increase in total observed exposure over 12 hours at the higher dose. When accounting for endogenous baseline, incremental Cmax also did not differ significantly (p = 0.062), and baseline-corrected iAUC0–12 remained similar between groups (p = 0.257). ( Comparison of pharmacokinetic parameters between dose groups shown in Table 2 ) Variability was substantially higher for baseline-corrected metrics (incremental Cmax and iAUC0–12), as reflected by the higher CV%, consistent with the known dissolution-limited and variable absorption of magnesium oxide. Table 2 Comparison of Pharmacokinetic Parameters Parameter 750 mg 2000 mg p-value* C0 (baseline) 0.826 ± 0.038 (CV 4.6%) 0.832 ± 0.069 (CV 8.2%) 0.797 Cmax 1.044 ± 0.095 (CV 9.1%) 0.986 ± 0.099 (CV 10.1%) 0.159 AUC0–12 11.069 ± 0.658 (CV 5.9%) 10.886 ± 0.893 (CV 8.2%) 0.573 Cavg0–12 (AUC/12) 0.922 ± 0.055 (CV 5.9%) 0.907 ± 0.074 (CV 8.2%) — Incremental Cmax (Cmax − C0) 0.218 ± 0.097 (CV 44.4%) 0.154 ± 0.053 (CV 34.6%) 0.062 iAUC0–12 1.156 ± 0.644 (CV 55.8%) 0.902 ± 0.388 (CV 43.0%) 0.257 Incremental Cavg0–12 0.096 ± 0.054 (CV 55.8%) 0.075 ± 0.032 (CV 43.0%) — Tmax (h), median (IQR) 6 (5–8) 2 (2–5) 0.025 Mean ± SD shown; CV indicates coefficient of variation. Tmax expressed as median (IQR). p-values calculated using t-test (all variables except Tmax) and Mann–Whitney U test (Tmax). Absorption Rate While overall exposure was not dose-proportional, the rate of absorption differed between groups: Tmax was significantly shorter in the 2000 mg group compared with the 750 mg group (median 2 h vs 6 h; p = 0.025), suggesting faster initial absorption at the higher dose shown in Table 2 . Mean concentration–time profiles showed a gradual rise across the observation period, consistent with slow dissolution and absorption of magnesium oxide (Fig. 2 A–B). Parameters Not Reliably Estimated A robust terminal log-linear elimination phase could not be confidently identified within the 0–12 h sampling window. Given the endogenous nature of magnesium and the absence of a distinct post-peak terminal decline, λz-dependent parameters (t1/2, AUC0–∞, CL/F, MRT) were not considered reliable and were not estimated. (Although such parameters can be derived from short studies when a clear, stable terminal decline with adequate quantifiable points is present, curves that continue to rise, plateau, or are dominated by baseline physiology yield unreliable estimates). Safety and Tolerability Both magnesium oxide doses were well tolerated. No serious adverse events or clinically significant changes in vital signs, laboratory tests, or electrocardiography were observed during the study. Importantly, gastrointestinal adverse effects such as nausea, vomiting, diarrhoea, or abdominal pain were not reported. These findings support a favourable safety profile for single oral doses of magnesium oxide at both 750 mg and 2000 mg in healthy adult males. The (Fig. 3 A-B ) illustrate the overall haemodynamic response Heart rate (Fig. 3 a) and Blood pressure (Fig. 3 b) following two oral doses of magnesium oxide over a 12-hour period. The 750 mg group shows no statistically significant changes in heart rate from baseline at any time point (all p > 0.05).The 2000 mg group demonstrates significant increases in heart rate at multiple time points compared with baseline (p < 0.05). Data indicate a dose-dependent physiological response with higher variability and significant elevations in the 2000 mg group. This line graph shows the trend of mean systolic and diastolic blood pressure over 12 hours following oral magnesium oxide administration (750 mg vs. 2000 mg). Both doses demonstrated stable systolic and diastolic values over time without clinically significant fluctuations. Slight transient variations were noted but remained within normal physiological limits. Discussion This study provides a rigorous, single-dose pharmacokinetic (PK) and safety evaluation of oral magnesium oxide (MgO) in healthy volunteers, yielding critical data on its absorption profile relevant to perioperative supplementation. Magnesium contributes to perioperative analgesia through multiple mechanisms. It reduces central sensitization via NMDA receptor antagonism and may additionally modulate neurochemical and stress responses that influence pain perception.[ 11 , 12 ] Our primary findings confirm the MgO exhibits non-linear, saturable absorption kinetics across the studied range. Despite a 2.67-fold dose increase (2000 mg vs 750 mg), systemic exposure did not increase proportionally, as reflected by the absence of statistically significant differences in Cmax and AUC0–12. This pattern was maintained after accounting for the endogenous nature of magnesium: incremental Cmax and baseline-corrected iAUC0–12 also remained similar between dose groups, with substantial inter-individual variability. Together, these results indicate a ceiling effect on MgO-related systemic magnesium delivery within this dose range.[ 13 ] Magnesium oxide is characterized by slow dissolution and limited bioavailability, which likely contributes to the gradual rise in serum magnesium across the 12-hour observation period. Importantly, while total exposure was not dose-proportional, the absorption rate appeared dose-dependent. The significantly shorter Tmax in the 2000 mg group (median 2 h) compared with the 750 mg group (median 6 h) suggests that a higher luminal magnesium load may accelerate early uptake without increasing overall absorbed fraction. A plausible explanation is the early engagement and relative saturation of regulated transcellular pathways with increasing reliance on passive paracellular flux, resulting in faster initial appearance of magnesium in the circulation but limited net gain in total systemic exposure. Mori et al. (2021) reported that approximately 15% of orally administered MgO is absorbed, with peak plasma concentrations occurring around 3 hours. [ 14 ] Baseline correction proved especially informative in this context. Because serum magnesium is endogenous and homeostatic ally regulated, observed concentration–time curves inherently incorporate both physiological background and dose-related increments. The larger coefficient of variation (CV) for baseline-corrected metrics (incremental Cmax and iAUC0–12) underscore the heterogeneous absorption of MgO From a clinical standpoint, both doses demonstrated excellent tolerability, with no reported gastrointestinal adverse effects or clinically meaningful safety signals. This is noteworthy given the common association of higher-dose MgO regimens with gastrointestinal intolerance in routine use. The absence of symptoms in this trial may reflect the single-dose design and controlled study conditions. Although the incremental increases in circulating magnesium were modest, such changes may still be relevant in perioperative settings where magnesium’s pharmacodynamic effects; particularly the neuromodulatory and analgesic mechanisms are not necessarily dependent on large absolute serum elevations. The significantly shorter T max in the 2000 mg group (median 2 vs.5 hours, p = 0.009) suggests that the higher luminal concentration facilitated quicker initial absorption. This is likely due to saturation of the active transcellular transport pathways (TRPM6/7), compelling the excess Mg 2+ to rely more heavily on the concentration gradient-driven passive paracellular diffusion across tight junctions[ 15 ]. However, this shift does not overcome the inherent ceiling on total uptake, resulting in the non-proportional C max and AUC. Our findings thus align with and refine the conclusions of Pardo et al. (2021) who confirmed that magnesium absorption is dose-dependent but saturable[ 16 ]. Both MgO doses were well tolerated with no reported gastrointestinal adverse effects. This is supported by Ivanovic et al., who showed that short-term MgO supplementation increased total and ionized serum magnesium without major electrolyte disturbances, reinforcing the physiological relevance and short-term safety of oral MgO[ 17 ]. The modest increases in serum magnesium observed in this study may still be relevant for perioperative supplementation. Magnesium has established roles in pain modulation, including attenuation of central sensitization through NMDA receptor antagonism. Evidence from perioperative studies of magnesium (including intravenous formulations) suggests that even modest changes in circulating magnesium can be associated with improved analgesic outcomes[ 18 , 19 ]. Similarly, prior oral supplementation studies have reported good tolerability with measurable increases in serum magnesium over comparable sampling windows. Taken together, these findings support the clinical plausibility of MgO as a preoperative supplementation strategy, although efficacy outcomes were not assessed in the present study Although systemic absorption of MgO is limited, unabsorbed luminal magnesium may interact with the gut environment and microbiota. This gut–brain axis hypothesis could represent a complementary pathway through which oral MgO might influence perioperative recovery, but requires dedicated mechanistic and clinical studies.[ 20 , 21 ] Serum magnesium concentrations increased gradually over the 0–12 h period in both dose groups, consistent with slow dissolution and absorption of magnesium oxide.[ 22 ] Because a robust terminal log-linear decline was not identifiable within this window, λz-dependent parameters were not estimated. This gradual absorption profile may be advantageous for perioperative use, where sustained rather than abrupt changes in circulating magnesium are desirable.[ 23 , 24 ] Several limitations should be acknowledged. The sampling window was limited to 12 hours, and a robust terminal log-linear phase was not clearly identifiable. Accordingly, λz-dependent parameters (t1/2, AUC0–∞, CL/F, MRT) were not estimated. While such parameters can be derived from short studies in the presence of a clear terminal decline with adequate quantifiable points and low extrapolated AUC, curves that continue to rise, plateau, or are strongly influenced by baseline physiology can yield unreliable estimates. Future studies incorporating longer sampling windows and potentially repeated dosing may better characterize the full absorption–elimination profile and help refine perioperative dosing strategies. Conclusion In summary, this study demonstrates that oral MgO displays rate differences without proportional exposure gains across 750–2000 mg, supporting a saturable absorption model with a practical ceiling on systemic delivery. These findings provide a pharmacokinetic rationale for cautious dose escalation and support the feasibility of MgO as a well-tolerated oral option for perioperative magnesium optimization. Abbreviations Declarations Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines. Ethical approval was obtained from the Institutional Ethics Committee, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India (Approval No. ECR/8958/INST/TN/2013/RR-19). Written informed consent was obtained from all participants prior to their inclusion in the study. CONSENT FOR PUBLICATION: I understand that the results of this research may be published in scientific journals or presented at conferences. I also understand that my personal identity, medical details, and individual investigation reports will remain strictly confidential and will not be disclosed in any publication or presentation. Only summarized, de-identified data will be used for scientific reporting. Statement of Consent for Publication I have been informed that the findings of this research may be published in academic journals or presented at professional meetings. All information used in reports or publications from this study will be kept strictly confidential. My name or any personal details will not appear anywhere in the published paper. I agree that the results from my participation may be used for scientific publication. AVAILABILITY OF DATA AND MATERIALS All data supporting the findings of this study are included within the article. COMPETING INTERESTS The authors declare that they have no competing interests. FUNDING This research did not receive any specific grant from funding agencies. AUTHORS’ CONTRIBUTIONS All authors contributed substantially to the conception, study design, data collection, analysis, and manuscript preparation. R.K.Swetha– Conceptualization, data collection, pharmacokinetic analysis, and drafting of the manuscript. Dr. B. Gayathri – Study design, supervision, critical revision of the manuscript, and correspondence. Dr. Vijayakumar T.M – Pharmacological interpretation and critical review of the discussion. All authors have read and approved the final manuscript and agree to be accountable for its content. ACKNOWLEDGEMENT Nil AUTHOR INFORMATION R.K.Swetha Lecturer, Department of Anaesthesiology SRM Medical College Hospital and Research Centre SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India Email: [email protected] ORCID: 0009-0001-9949-6100 Dr. B. Gayathri (Corresponding Author) Professor and Head, Department of Anaesthesiology SRM Medical College Hospital and Research Centre SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India Email: [email protected] Phone: +91-9500092905 ORCID: 0000-0001-7992-5855 Dr. Vijayakumar T.M Professor and Head, Department of Pharmacy Practice SRM College of Pharmacy, SRM Institute of Science and Technology, Tamil Nadu, India Email: [email protected] ORCID: 0000-0002-7749-3224 References Fiorentini D, Cappadone C, Farruggia G, Prata C. Magnesium: biochemistry, nutrition, detection, and social impact of diseases linked to its deficiency. Nutrients. 2021 Mar 30;13(4):1136. Fatima G, Dzupina A, Alhmadi HB, Magomedova A, Siddiqui Z, Mehdi A, Hadi N, RAZA AM. Magnesium matters: A comprehensive review of its vital role in health and diseases. Cureus. 2024 Oct 13;16(10). Shekhar S, Singh RB, Lata S, Singh A, De RR, Sharma P, Sinha S, SINGH RB, rana De R, SINHA S. Prevalence of Hypomagnesemia in ICU Patients at a Tertiary Care Center: A Prospective Observational Study. Cureus. 2025 Apr 3;17(4). Avci Y, Rajarathinam M, Kalsekar N, Tawfic Q, Krause S, Nguyen D, Liu E, Nagappa M, Subramani Y. Unravelling the analgesic effects of perioperative magnesium in general abdominal surgery: a systematic review and meta-analysis of randomized controlled trials. Brazilian Journal of Anesthesiology. 2024 Aug 12;74:844524. Kulik K, Żyżyńska-Granica B, Kowalczyk A, Kurowski P, Gajewska M, Bujalska-Zadrożny M. Magnesium and morphine in the treatment of chronic neuropathic pain–A biomedical mechanism of action. International Journal of Molecular Sciences. 2021 Dec 18;22(24):13599. Blancquaert L, Vervaet C, Derave W. Predicting and testing bioavailability of magnesium supplements. Nutrients. 2019 Jul 20;11(7):1663. Gommers LM, Hoenderop JG, de Baaij JH. Mechanisms of proton pump inhibitor‐induced hypomagnesemia. Acta Physiologica. 2022 Aug;235(4):e13846. Chamniansawat S, Suksridechacin N, Thongon N. Current opinion on the regulation of small intestinal magnesium absorption. World Journal of Gastroenterology. 2023 Jan 14;29(2):332. D’Souza RF, Surapaneni KM. New standards, new vision: Directing modern medical research as per the 2024 revised Declaration of Helsinki. Asian Journal of Psychiatry. 2025 Feb 1;104:104363. Huang HH, Liao KY, Zhao MJ, Agoram B, Chaturvedula A. Clinical Trial Simulation to Assess Sample Size and Power For Detecting Differences in Pharmacokinetic Exposure Metrics. InAmerican Conference of Pharmacometrics 2024 Nov 10. International Society of Pharmacometrics. Konarska A, Fabijański A, Dukacz A, Firlej W, Rychlewska-Duda J, Lisiecka J, Nowak M, Janik M, Ufnalska B, Machowiak A. Magnesium in pain control-mechanisms of action in perioperative pain, neuropathic pain and migraine. Journal of Education, Health and Sport. 2025 Feb 6;78:57571. Pickering G, Noah L, Pereira B, Goubayon J, Leray V, Touron A, Macian N, Bernard L, Dualé C, Roux V, Chassain C. Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: An fMRI study. Frontiers in Nutrition. 2023 Aug 16;10:1211321 Mori H, Tack J, Suzuki H. Magnesium oxide in constipation. Nutrients. 2021 Jan 28;13(2):421 Mori H, Suzuki H, Hirai Y, Okuzawa A, Kayashima A, Kubosawa Y, Kinoshita S, Fujimoto A, Nakazato Y, Nishizawa T, Kikuchi M. Clinical features of hypermagnesemia in patients with functional constipation taking daily magnesium oxide. Journal of clinical biochemistry and nutrition. 2019;65(1):76-81 Kröse JL, de Baaij JH. Magnesium biology. Nephrology Dialysis Transplantation. 2024 Dec;39(12):1965-75. Pardo MR, Vilar EG, Martín IS, Martín MA. Bioavailability of magnesium food supplements: A systematic review. Nutrition. 2021 Sep 1;89:111294. Ivanovic ND, Radosavljevic B, Zekovic M, Korcok D, Ignjatovic S, Djordjevic B, Milinkovic N. Effects of short-term magnesium supplementation on ionized, total magnesium and other relevant electrolytes levels. Biometals. 2022 Apr;35(2):267-83 Salkaya A, Oba S, Altınay M, Türk HŞ, Kılınç L, Yılmaz A. The effects of perioperative low-dose magnesium sulfate infusion on postoperative pain in lumbar surgery. Signa Vitae. 2024 Jan 1;20(1). Rooney MR, Rudser KD, Alonso A, Harnack L, Saenger AK, Lutsey PL. Circulating ionized magnesium: comparisons with circulating total magnesium and the response to magnesium supplementation in a randomized controlled trial. Nutrients. 2020 Jan 20;12(1):263 Portincasa P, Bonfrate L, Vacca M, De Angelis M, Farella I, Lanza E, Khalil M, Wang DQ, Sperandio M, Di Ciaula A. Gut microbiota and short chain fatty acids: implications in glucose homeostasis. International journal of molecular sciences. 2022 Jan 20;23(3):1105 Zhao M, Zhang L, Liu Z. Gut microbiota-mediated pain sensitization: mechanisms and therapeutic implications. Frontiers in Pain Research. 2025 Jul 3;6:1626515 Carney SL, Wong NL, Quamme GA, Dirks JH. Effect of magnesium deficiency on renal magnesium and calcium transport in the rat. The Journal of Clinical Investigation. 1980 Jan 1;65(1):180-8. Edinoff AN, Fitz-Gerald JS, Holland KA, Reed JG, Murnane SE, Minter SG, Kaye AJ, Cornett EM, Imani F, Khademi SH, Kaye AM. Adjuvant drugs for peripheral nerve blocks: The role of NMDA antagonists, neostigmine, epinephrine, and sodium bicarbonate. Anesthesiology and Pain Medicine. 2021 Jul 5;11(3):e117146. Jin Z, Zhao J. Effectiveness and impact of intravenous magnesium sulfate in spinal surgery systematic review and meta-analysis. Frontiers in Pharmacology. 2025 Jun 18;16:1624119. 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Science and Technology (Deemed to be University) SRM Medical College Hospital and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Swetha","middleName":"","lastName":"RK","suffix":""},{"id":561912302,"identity":"10253267-9ca2-4a13-b758-716e15c8d86c","order_by":2,"name":"Vijaykumar TM","email":"","orcid":"","institution":"SRM Institute of Science and Technology (Deemed to be University) College of Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Vijaykumar","middleName":"","lastName":"TM","suffix":""},{"id":561912303,"identity":"9cf077b9-1528-46e5-a302-bcafc7df0fd3","order_by":3,"name":"Sananthya K","email":"","orcid":"","institution":"SRM Medical College Hospital and Research Centre: SRM Institute of Science and Technology (Deemed to be University) SRM Medical College Hospital and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Sananthya","middleName":"","lastName":"K","suffix":""}],"badges":[],"createdAt":"2025-12-11 09:46:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8335012/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8335012/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98609513,"identity":"111e6f3d-9aaa-4cdc-98f7-885b30360b83","added_by":"auto","created_at":"2025-12-19 14:11:42","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":9278,"visible":true,"origin":"","legend":"","description":"","filename":"jtrmJTRMD2522121.xml","url":"https://assets-eu.researchsquare.com/files/rs-8335012/v1/b608bb2194ce7dc45d93b114.xml"},{"id":98609516,"identity":"924968ed-48bd-4a0c-b689-4cec4ee9366b","added_by":"auto","created_at":"2025-12-19 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14:11:42","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99499,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8335012/v1/58009414ab43bbc13c1c1458.html"},{"id":98609514,"identity":"1dd1d5f4-9b77-4cb0-bc51-3df50f02b8db","added_by":"auto","created_at":"2025-12-19 14:11:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70322,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCONSORT Flow Diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFlow diagram of the progress through the phases of a randomised trial of two groups (that is, enrolment, intervention allocation, follow-up, and data analysis) \u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8335012/v1/2b45ae9eff1c90a8d659fda1.png"},{"id":98609512,"identity":"6e5efcdd-8ef6-4bbd-8f4f-e85efb46355a","added_by":"auto","created_at":"2025-12-19 14:11:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":85187,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e:Values are shown as mean ± SD of serum magnesium at each time point. Error bars represent standard deviation for both dose groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e: Data are shown as mean ± SD of baseline-corrected serum magnesium (Ct – C0). Error bars indicate standard deviation for both groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8335012/v1/ea0e7be39cd37d0c1fa6a3cf.png"},{"id":98609511,"identity":"feac826e-b54a-4ccc-a45e-8d53229cae94","added_by":"auto","created_at":"2025-12-19 14:11:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":100265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e:Mean heart rate trends over time after administration of 750 mg and 2000 mg of oral magnesium oxide.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e: Mean systolic and diastolic blood pressure values over time for the 750 mg and 2000 mg magnesium dose groups\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8335012/v1/c10221d40e62e7b3f3a1af05.png"},{"id":99797614,"identity":"d503de77-ec98-4176-9bf6-8890a750a2fc","added_by":"auto","created_at":"2026-01-08 13:46:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1047353,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8335012/v1/b6efe460-f107-4148-becf-45549eec2e3b.pdf"}],"financialInterests":"","formattedTitle":"Randomized, Open-Label Pharmacokinetic Study of Oral Magnesium Oxide in Healthy Volunteers","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMagnesium is the second most abundant intracellular cation and serves as an essential cofactor for over 300 enzymatic reactions regulating diverse physiological processes[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Maintaining adequate magnesium levels is crucial for normal cellular and systemic function [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hypomagnesemia is highly prevalent, affecting 10\u0026ndash;30% of the general population and up to 60% of critically ill patients[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].This deficiency is significantly associated with increased postoperative pain, cardiac arrhythmias, and prolonged recovery, underscoring magnesium\u0026rsquo;s vital role in perioperative care[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Consequently, magnesium administration, valued for its analgesic, neuroprotective, and antiarrhythmic properties through mechanisms like antagonism of N-methyl-D-aspartate (NMDA) receptors, has become integral to Enhanced Recovery After Surgery (ERAS) protocols.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eMagnesium oxide (MgO) is widely used for magnesium supplementation due to its high elemental content and affordability. However, MgO exhibits inherently low aqueous solubility, resulting in a low systemic bioavailability, typically estimated between 4\u0026ndash;10%. Despite its clinical importance, comprehensive data characterizing the pharmacokinetics (PK) and dose proportionality of oral MgO are sparse and inconsistent[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The poor solubility requires gastric acid for conversion into absorbable magnesium ions, which complicates absorption kinetics, and previous studies have lacked the detailed characterization needed to optimize dosing regimens[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study was designed to rigorously evaluate the safety and single-dose pharmacokinetic profiles of oral magnesium oxide at two distinct dosage levels: 750 mg and 2000 mg in healthy male volunteers. The primary objective was to fully characterize key PK parameters, including peak plasma concentration (Cmax), time to peak concentration (T max), and area under the concentration-time curve (AUC), to determine if systemic exposure increases proportionally with the dose. We specifically hypothesized that the intestinal absorption of MgO would exhibit non-linear, saturable kinetics driven by the limited capacity of transcellular transport pathways.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a randomized, open-label pharmacokinetic study conducted at the Clinical Trial and Research Unit, SRM Medical College Hospital and Research Centre. The study adhered to the principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice (ICH-GCP) [9]. Ethical approval was obtained from the Institutional Ethics Committee (Approval No. ECR8958INSTTN2013RR-19), and the study was registered prospectively with the Clinical Trials Registry - India (CTRI/2025/02/081449). All participants provided written informed consent before enrolment. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-four healthy male volunteers aged 18-45 years, weighing at least 50 kg, were recruited. Eligibility criteria included normal clinical evaluation and laboratory tests, no history of smoking or alcohol intake, and no use of medication or supplements that could influence magnesium pharmacokinetics for at least 14 days prior to enrolment. Exclusion criteria encompassed systemic disorders (diabetes mellitus, hypertension, tuberculosis), clinically significant abnormalities in hepatic, renal, cardiac, gastrointestinal, neurological, endocrine, respiratory, metabolic, psychiatric, or haematological function, recent surgery, substance abuse, known hypersensitivity to magnesium compounds, participation in other clinical trials within 3 months, and significant blood donation or loss within the preceding three months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were randomized using a simple randomization method into two equal groups (n=12 each) to receive a single oral dose of either 750 mg or 2000 mg of magnesium oxide\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure\u003c/strong\u003e\u003cbr\u003eVolunteers fasted overnight for at least 8 hours before dosing to minimize dietary confounding on magnesium absorption. On the study day, participants received the assigned magnesium oxide dose orally with 200 mL of water in a seated position under continuous medical supervision. Standard meals were provided after one-hour post-dose\u003cstrong\u003e.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003e\u003cstrong\u003eParticipant recruitment and flow through the study are shown\u0026nbsp;in\u0026nbsp;Figure\u0026nbsp;1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Collection and Processing\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Venous blood samples (2 mL) were collected at baseline (pre-dose, T=0) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4-, 6-, 8-, and 12-hours post-dose via an indwelling catheter. Blood was collected into heparinized tubes, centrifuged within 30 minutes to separate plasma, which was stored at 2-8\u0026deg;C and analyzed on the same day. Haemolyzed or lipemic samples were excluded from analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssay Method\u003cbr\u003e\u003c/strong\u003ePlasma magnesium concentrations were assessed using a validated colorimetric assay based on complex formation with xylidyl blue in an alkaline medium, measured by Beckman AU480/AU680 analyzers. Calcium interference was blocked by adding GEDTA. The assay exhibited linearity between 0.5 and 8 mg/dL, with between-day variation under 5% and accuracy better than 10%. Detection and quantification limits were 0.1 and 0.5 mg/dL, respectively. Calibration was performed weekly or with each lot change.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePharmacokinetic Analysis\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Pharmacokinetic parameters were calculated using PK Solutions 2.0 (Summit Research Services, Montrose, Colorado, USA). Primary parameters included peak plasma concentration (Cmax) and time to peak concentration (Tmax). The area under the plasma concentration-time curve was calculated from time zero to last measurable concentration (AUC_t) using the linear trapezoidal rule and extended to infinity (AUC_inf) by extrapolation using the elimination rate constant (kel), derived from the terminal log-linear slope. Elimination half-life (t_1/2) was calculated as 0.693/kel. Additional parameters included mean residence time (MRT) and apparent oral clearance (Cl/F). Inter-individual variability was expressed as coefficient of variation (CV).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data were assessed for normality using the Shapiro-Wilk test and confirmed for normality. The data which are normally distributed are summarized as mean \u0026plusmn; standard deviation and for not normally distributed variables are summarized as median with interquartile range accordingly. Group comparisons for non-normally distributed data utilized the Mann-Whitney U test. Comparisons of each time point with baseline values were performed using a paired t-test.\u003c/p\u003e\n\u003cp\u003eA sample size of 24 was calculated for a 80% power to detect, at a 5% significance level, and 1.15 as the effect size (Cohen\u0026rsquo;s d) [10]. Data analysis was performed using IBM Statistical Package for the Social Sciences (SPSS) software, version 26.0 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Monitoring\u003cbr\u003e\u003c/strong\u003eVital signs were recorded throughout the study period. Laboratory safety evaluations included electrocardiography (ECG), renal and hepatic function tests, complete blood count, and serum electrolytes. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and abdominal discomfort were closely monitored. Any adverse events were documented. Participants received compensation consistent with ethical committee guidelines.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eParticipant Characteristics\u003c/h2\u003e \u003cp\u003eA total of 24 healthy male volunteers were enrolled and randomized evenly into two groups receiving 750 mg (Group 1) or 2000 mg (Group 2) of oral magnesium oxide. All participants completed the study and provided evaluable pharmacokinetic data. Baseline demographic and clinical characteristics were comparable between groups with no statistically significant differences. (\u003cb\u003eBaseline demographics of the participants shown in\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e).\u003c/b\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\u003eBaseline demographic and clinical characteristics of the participants.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup1 (750 mg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup 2 (2000 mg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.812\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e170.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e166.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.342\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e63.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e64.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.789\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.456\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. There were no statistically significant differences between the groups.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn terms of the remaining baseline clinical characteristics, serum magnesium levels were comparable between Group 1 (750 mg) and Group 2 (2000 mg), with mean values of 1.95\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12 mg/dL and 1.97\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17 mg/dL, respectively (p\u0026thinsp;=\u0026thinsp;0.891). Blood glucose levels were also similar across groups, with Group 1 showing 95.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.6 mg/dL and Group 2 showing 87.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 mg/dL (p\u0026thinsp;=\u0026thinsp;0.134). There was no statistically significant difference in hemoglobin concentration, which measured 15.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3 g/dL in Group 1 and 15.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 g/dL in Group 2 (p\u0026thinsp;=\u0026thinsp;0.567). Similarly, red blood cell (RBC) counts (Group 1: 5.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39 \u0026times;10⁶/\u0026micro;L; Group 2: 5.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30 \u0026times;10⁶/\u0026micro;L) and white blood cell (WBC) counts (Group 1: 7511\u0026thinsp;\u0026plusmn;\u0026thinsp;2203 cells/\u0026micro;L; Group 2: 6388\u0026thinsp;\u0026plusmn;\u0026thinsp;1223 cells/\u0026micro;L) did not differ significantly between the groups (p\u0026thinsp;=\u0026thinsp;0.623 and p\u0026thinsp;=\u0026thinsp;0.289, respectively).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetic Parameters\u003c/h2\u003e \u003cp\u003eNon-compartmental analysis over the 0\u0026ndash;12 h demonstrated non-dose-proportional systemic exposure of magnesium following oral magnesium oxide, consistent with saturable, non-linear absorption. Because magnesium is an endogenous analyte, both observed and baseline-corrected (incremental) analyses were performed using each subject\u0026rsquo;s pre-dose concentration at 0 h (C0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eNon-Proportionality in Systemic Exposure\u003c/h2\u003e \u003cp\u003eDespite a 2.67-fold increase in the administered dose, the systemic delivery of magnesium did not increase proportionally. The key exposure parameters were similar across groups\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eCmax was not significantly different between the 750 mg and 2000 mg groups (p\u0026thinsp;=\u0026thinsp;0.159).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAUC0\u0026ndash;12 was comparable between treatment arms (p\u0026thinsp;=\u0026thinsp;0.573), indicating no meaningful increase in total observed exposure over 12 hours at the higher dose.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhen accounting for endogenous baseline, incremental Cmax also did not differ significantly (p\u0026thinsp;=\u0026thinsp;0.062), and baseline-corrected iAUC0\u0026ndash;12 remained similar between groups (p\u0026thinsp;=\u0026thinsp;0.257). (\u003cb\u003eComparison of pharmacokinetic parameters between dose groups shown in\u003c/b\u003e Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eVariability was substantially higher for baseline-corrected metrics (incremental Cmax and iAUC0\u0026ndash;12), as reflected by the higher CV%, consistent with the known dissolution-limited and variable absorption of magnesium oxide.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \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\u003eComparison of Pharmacokinetic Parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e750 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2000 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC0 (baseline)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.826\u0026thinsp;\u0026plusmn;\u0026thinsp;0.038 (CV 4.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.832\u0026thinsp;\u0026plusmn;\u0026thinsp;0.069 (CV 8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.797\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCmax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.044\u0026thinsp;\u0026plusmn;\u0026thinsp;0.095 (CV 9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.986\u0026thinsp;\u0026plusmn;\u0026thinsp;0.099 (CV 10.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.159\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC0\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.069\u0026thinsp;\u0026plusmn;\u0026thinsp;0.658 (CV 5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.886\u0026thinsp;\u0026plusmn;\u0026thinsp;0.893 (CV 8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCavg0\u0026ndash;12 (AUC/12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.922\u0026thinsp;\u0026plusmn;\u0026thinsp;0.055 (CV 5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.907\u0026thinsp;\u0026plusmn;\u0026thinsp;0.074 (CV 8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIncremental Cmax (Cmax\u0026thinsp;\u0026minus;\u0026thinsp;C0)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.218\u0026thinsp;\u0026plusmn;\u0026thinsp;0.097 (CV 44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.154\u0026thinsp;\u0026plusmn;\u0026thinsp;0.053 (CV 34.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eiAUC0\u0026ndash;12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.156\u0026thinsp;\u0026plusmn;\u0026thinsp;0.644 (CV 55.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.902\u0026thinsp;\u0026plusmn;\u0026thinsp;0.388 (CV 43.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.257\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncremental Cavg0\u0026ndash;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.096\u0026thinsp;\u0026plusmn;\u0026thinsp;0.054 (CV 55.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.075\u0026thinsp;\u0026plusmn;\u0026thinsp;0.032 (CV 43.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTmax (h), median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6 (5\u0026ndash;8)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e2 (2\u0026ndash;5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD shown; CV indicates coefficient of variation. Tmax expressed as median (IQR). p-values calculated using t-test (all variables except Tmax) and Mann\u0026ndash;Whitney U test (Tmax).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAbsorption Rate\u003c/h2\u003e \u003cp\u003eWhile overall exposure was not dose-proportional, the rate of absorption differed between groups:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTmax was significantly shorter in the 2000 mg group compared with the 750 mg group (median 2 h vs 6 h; p\u0026thinsp;=\u0026thinsp;0.025), suggesting faster initial absorption at the higher dose shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMean concentration\u0026ndash;time profiles showed a gradual rise across the observation period, consistent with slow dissolution and absorption of magnesium oxide (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026ndash;B).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eParameters Not Reliably Estimated\u003c/h2\u003e \u003cp\u003eA robust terminal log-linear elimination phase could not be confidently identified within the 0\u0026ndash;12 h sampling window. Given the endogenous nature of magnesium and the absence of a distinct post-peak terminal decline, λz-dependent parameters (t1/2, AUC0\u0026ndash;\u0026infin;, CL/F, MRT) were not considered reliable and were not estimated. (Although such parameters can be derived from short studies when a clear, stable terminal decline with adequate quantifiable points is present, curves that continue to rise, plateau, or are dominated by baseline physiology yield unreliable estimates).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSafety and Tolerability\u003c/h2\u003e \u003cp\u003eBoth magnesium oxide doses were well tolerated. No serious adverse events or clinically significant changes in vital signs, laboratory tests, or electrocardiography were observed during the study. Importantly, gastrointestinal adverse effects such as nausea, vomiting, diarrhoea, or abdominal pain were not reported. These findings support a favourable safety profile for single oral doses of magnesium oxide at both 750 mg and 2000 mg in healthy adult males.\u003c/p\u003e \u003cp\u003eThe (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B\u003cb\u003e)\u003c/b\u003e illustrate the overall haemodynamic response Heart rate (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) and Blood pressure (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eb) following two oral doses of magnesium oxide over a 12-hour period.\u003c/p\u003e \u003cp\u003eThe 750 mg group shows no statistically significant changes in heart rate from baseline at any time point (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).The 2000 mg group demonstrates significant increases in heart rate at multiple time points compared with baseline (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Data indicate a dose-dependent physiological response with higher variability and significant elevations in the 2000 mg group.\u003c/p\u003e \u003cp\u003eThis line graph shows the trend of mean systolic and diastolic blood pressure over 12 hours following oral magnesium oxide administration (750 mg vs. 2000 mg). Both doses demonstrated stable systolic and diastolic values over time without clinically significant fluctuations. Slight transient variations were noted but remained within normal physiological limits.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a rigorous, single-dose pharmacokinetic (PK) and safety evaluation of oral magnesium oxide (MgO) in healthy volunteers, yielding critical data on its absorption profile relevant to perioperative supplementation. Magnesium contributes to perioperative analgesia through multiple mechanisms. It reduces central sensitization via NMDA receptor antagonism and may additionally modulate neurochemical and stress responses that influence pain perception.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOur primary findings confirm the MgO exhibits non-linear, saturable absorption kinetics across the studied range. Despite a 2.67-fold dose increase (2000 mg vs 750 mg), systemic exposure did not increase proportionally, as reflected by the absence of statistically significant differences in Cmax and AUC0\u0026ndash;12. This pattern was maintained after accounting for the endogenous nature of magnesium: incremental Cmax and baseline-corrected iAUC0\u0026ndash;12 also remained similar between dose groups, with substantial inter-individual variability. Together, these results indicate a ceiling effect on MgO-related systemic magnesium delivery within this dose range.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eMagnesium oxide is characterized by slow dissolution and limited bioavailability, which likely contributes to the gradual rise in serum magnesium across the 12-hour observation period. Importantly, while total exposure was not dose-proportional, the absorption rate appeared dose-dependent. The significantly shorter Tmax in the 2000 mg group (median 2 h) compared with the 750 mg group (median 6 h) suggests that a higher luminal magnesium load may accelerate early uptake without increasing overall absorbed fraction. A plausible explanation is the early engagement and relative saturation of regulated transcellular pathways with increasing reliance on passive paracellular flux, resulting in faster initial appearance of magnesium in the circulation but limited net gain in total systemic exposure. Mori et al. (2021) reported that approximately 15% of orally administered MgO is absorbed, with peak plasma concentrations occurring around 3 hours. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eBaseline correction proved especially informative in this context. Because serum magnesium is endogenous and homeostatic ally regulated, observed concentration\u0026ndash;time curves inherently incorporate both physiological background and dose-related increments. The larger coefficient of variation (CV) for baseline-corrected metrics (incremental Cmax and iAUC0\u0026ndash;12) underscore the heterogeneous absorption of MgO\u003c/p\u003e \u003cp\u003eFrom a clinical standpoint, both doses demonstrated excellent tolerability, with no reported gastrointestinal adverse effects or clinically meaningful safety signals. This is noteworthy given the common association of higher-dose MgO regimens with gastrointestinal intolerance in routine use. The absence of symptoms in this trial may reflect the single-dose design and controlled study conditions. Although the incremental increases in circulating magnesium were modest, such changes may still be relevant in perioperative settings where magnesium\u0026rsquo;s pharmacodynamic effects; particularly the neuromodulatory and analgesic mechanisms are not necessarily dependent on large absolute serum elevations.\u003c/p\u003e \u003cp\u003eThe significantly shorter T\u003csub\u003emax\u003c/sub\u003e in the 2000 mg group (median 2 vs.5 hours, p\u0026thinsp;=\u0026thinsp;0.009) suggests that the higher luminal concentration facilitated quicker initial absorption. This is likely due to saturation of the active transcellular transport pathways (TRPM6/7), compelling the excess Mg\u003csup\u003e2+\u003c/sup\u003e to rely more heavily on the concentration gradient-driven passive paracellular diffusion across tight junctions[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, this shift does not overcome the inherent ceiling on total uptake, resulting in the non-proportional C\u003csub\u003emax\u003c/sub\u003e and AUC. Our findings thus align with and refine the conclusions of Pardo et al. (2021) who confirmed that magnesium absorption is dose-dependent but saturable[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBoth MgO doses were well tolerated with no reported gastrointestinal adverse effects. This is supported by Ivanovic et al., who showed that short-term MgO supplementation increased total and ionized serum magnesium without major electrolyte disturbances, reinforcing the physiological relevance and short-term safety of oral MgO[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe modest increases in serum magnesium observed in this study may still be relevant for perioperative supplementation. Magnesium has established roles in pain modulation, including attenuation of central sensitization through NMDA receptor antagonism. Evidence from perioperative studies of magnesium (including intravenous formulations) suggests that even modest changes in circulating magnesium can be associated with improved analgesic outcomes[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Similarly, prior oral supplementation studies have reported good tolerability with measurable increases in serum magnesium over comparable sampling windows. Taken together, these findings support the clinical plausibility of MgO as a preoperative supplementation strategy, although efficacy outcomes were not assessed in the present study\u003c/p\u003e \u003cp\u003eAlthough systemic absorption of MgO is limited, unabsorbed luminal magnesium may interact with the gut environment and microbiota. This gut\u0026ndash;brain axis hypothesis could represent a complementary pathway through which oral MgO might influence perioperative recovery, but requires dedicated mechanistic and clinical studies.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSerum magnesium concentrations increased gradually over the 0\u0026ndash;12 h period in both dose groups, consistent with slow dissolution and absorption of magnesium oxide.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Because a robust terminal log-linear decline was not identifiable within this window, λz-dependent parameters were not estimated. This gradual absorption profile may be advantageous for perioperative use, where sustained rather than abrupt changes in circulating magnesium are desirable.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The sampling window was limited to 12 hours, and a robust terminal log-linear phase was not clearly identifiable. Accordingly, λz-dependent parameters (t1/2, AUC0\u0026ndash;\u0026infin;, CL/F, MRT) were not estimated. While such parameters can be derived from short studies in the presence of a clear terminal decline with adequate quantifiable points and low extrapolated AUC, curves that continue to rise, plateau, or are strongly influenced by baseline physiology can yield unreliable estimates. Future studies incorporating longer sampling windows and potentially repeated dosing may better characterize the full absorption\u0026ndash;elimination profile and help refine perioperative dosing strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this study demonstrates that oral MgO displays rate differences without proportional exposure gains across 750\u0026ndash;2000 mg, supporting a saturable absorption model with a practical ceiling on systemic delivery. These findings provide a pharmacokinetic rationale for cautious dose escalation and support the feasibility of MgO as a well-tolerated oral option for perioperative magnesium optimization.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/58895_8739fc6c57c1c19a/58895_custom_files/img1766152774.png\" width=\"747\" height=\"967\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice (ICH-GCP) guidelines. Ethical approval was obtained from the Institutional Ethics Committee, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India (Approval No. ECR/8958/INST/TN/2013/RR-19). Written informed consent was obtained from all participants prior to their inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI understand that the results of this research may be published in scientific journals or presented at conferences. I also understand that my personal identity, medical details, and individual investigation reports will remain strictly confidential and will not be disclosed in any publication or presentation. Only summarized, de-identified data will be used for scientific reporting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Consent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI have been informed that the findings of this research may be published in academic journals or presented at professional meetings. All information used in reports or publications from this study will be kept strictly confidential. My name or any personal details will not appear anywhere in the published paper. I agree that the results from my participation may be used for scientific publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting the findings of this study are included within the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS\u0026rsquo; CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed substantially to the conception, study design, data collection, analysis, and manuscript preparation.\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eR.K.Swetha\u0026ndash; Conceptualization, data collection, pharmacokinetic analysis, and drafting of the manuscript.\u003c/li\u003e\n \u003cli\u003eDr. B. Gayathri \u0026ndash; Study design, supervision, critical revision of the manuscript, and correspondence.\u003c/li\u003e\n \u003cli\u003eDr. Vijayakumar T.M \u0026ndash; Pharmacological interpretation and critical review of the discussion.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript and agree to be accountable for its content.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNil\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003e\u003cstrong\u003eR.K.Swetha\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eLecturer, Department of Anaesthesiology\u003cbr\u003e\u0026nbsp;SRM Medical College Hospital and Research Centre\u003cbr\u003e\u0026nbsp;SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India\u003cbr\u003e\u0026nbsp;Email: [email protected]\u003cbr\u003e\u0026nbsp;ORCID: 0009-0001-9949-6100\u003c/p\u003e\n\u003col start=\"2\" type=\"1\"\u003e\n \u003cli\u003e\u003cstrong\u003eDr. B. Gayathri (Corresponding Author)\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Professor and Head, Department of Anaesthesiology\u003cbr\u003e\u0026nbsp;SRM Medical College Hospital and Research Centre\u003cbr\u003e\u0026nbsp;SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India\u003cbr\u003e\u0026nbsp;Email: [email protected]\u003cbr\u003e\u0026nbsp;Phone: +91-9500092905\u003cbr\u003e\u0026nbsp;ORCID: 0000-0001-7992-5855\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDr. Vijayakumar T.M\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Professor and Head, Department of Pharmacy Practice\u003cbr\u003e\u0026nbsp;SRM College of Pharmacy, SRM Institute of Science and Technology, Tamil Nadu, India\u003cbr\u003e\u0026nbsp;Email: [email protected]\u003cbr\u003e\u0026nbsp;ORCID: 0000-0002-7749-3224\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFiorentini D, Cappadone C, Farruggia G, Prata C. Magnesium: biochemistry, nutrition, detection, and social impact of diseases linked to its deficiency. Nutrients. 2021 Mar 30;13(4):1136.\u003c/li\u003e\n \u003cli\u003eFatima G, Dzupina A, Alhmadi HB, Magomedova A, Siddiqui Z, Mehdi A, Hadi N, RAZA AM. Magnesium matters: A comprehensive review of its vital role in health and diseases. Cureus. 2024 Oct 13;16(10).\u003c/li\u003e\n \u003cli\u003eShekhar S, Singh RB, Lata S, Singh A, De RR, Sharma P, Sinha S, SINGH RB, rana De R, SINHA S. Prevalence of Hypomagnesemia in ICU Patients at a Tertiary Care Center: A Prospective Observational Study. Cureus. 2025 Apr 3;17(4).\u003c/li\u003e\n \u003cli\u003eAvci Y, Rajarathinam M, Kalsekar N, Tawfic Q, Krause S, Nguyen D, Liu E, Nagappa M, Subramani Y. Unravelling the analgesic effects of perioperative magnesium in general abdominal surgery: a systematic review and meta-analysis of randomized controlled trials. Brazilian Journal of Anesthesiology. 2024 Aug 12;74:844524.\u003c/li\u003e\n \u003cli\u003eKulik K, Żyżyńska-Granica B, Kowalczyk A, Kurowski P, Gajewska M, Bujalska-Zadrożny M. Magnesium and morphine in the treatment of chronic neuropathic pain\u0026ndash;A biomedical mechanism of action. International Journal of Molecular Sciences. 2021 Dec 18;22(24):13599.\u003c/li\u003e\n \u003cli\u003eBlancquaert L, Vervaet C, Derave W. Predicting and testing bioavailability of magnesium supplements. Nutrients. 2019 Jul 20;11(7):1663.\u003c/li\u003e\n \u003cli\u003eGommers LM, Hoenderop JG, de Baaij JH. Mechanisms of proton pump inhibitor‐induced hypomagnesemia. Acta Physiologica. 2022 Aug;235(4):e13846.\u003c/li\u003e\n \u003cli\u003eChamniansawat S, Suksridechacin N, Thongon N. Current opinion on the regulation of small intestinal magnesium absorption. World Journal of Gastroenterology. 2023 Jan 14;29(2):332.\u003c/li\u003e\n \u003cli\u003eD\u0026rsquo;Souza RF, Surapaneni KM. New standards, new vision: Directing modern medical research as per the 2024 revised Declaration of Helsinki. Asian Journal of Psychiatry. 2025 Feb 1;104:104363.\u003c/li\u003e\n \u003cli\u003eHuang HH, Liao KY, Zhao MJ, Agoram B, Chaturvedula A. Clinical Trial Simulation to Assess Sample Size and Power For Detecting Differences in Pharmacokinetic Exposure Metrics. InAmerican Conference of Pharmacometrics 2024 Nov 10. International Society of Pharmacometrics.\u003c/li\u003e\n \u003cli\u003eKonarska A, Fabijański A, Dukacz A, Firlej W, Rychlewska-Duda J, Lisiecka J, Nowak M, Janik M, Ufnalska B, Machowiak A. Magnesium in pain control-mechanisms of action in perioperative pain, neuropathic pain and migraine. Journal of Education, Health and Sport. 2025 Feb 6;78:57571.\u003c/li\u003e\n \u003cli\u003ePickering G, Noah L, Pereira B, Goubayon J, Leray V, Touron A, Macian N, Bernard L, Dual\u0026eacute; C, Roux V, Chassain C. Assessing brain function in stressed healthy individuals following the use of a combination of green tea, Rhodiola, magnesium, and B vitamins: An fMRI study. Frontiers in Nutrition. 2023 Aug 16;10:1211321\u003c/li\u003e\n \u003cli\u003eMori H, Tack J, Suzuki H. Magnesium oxide in constipation. Nutrients. 2021 Jan 28;13(2):421\u003c/li\u003e\n \u003cli\u003eMori H, Suzuki H, Hirai Y, Okuzawa A, Kayashima A, Kubosawa Y, Kinoshita S, Fujimoto A, Nakazato Y, Nishizawa T, Kikuchi M. Clinical features of hypermagnesemia in patients with functional constipation taking daily magnesium oxide. Journal of clinical biochemistry and nutrition. 2019;65(1):76-81\u003c/li\u003e\n \u003cli\u003eKr\u0026ouml;se JL, de Baaij JH. Magnesium biology. Nephrology Dialysis Transplantation. 2024 Dec;39(12):1965-75.\u003c/li\u003e\n \u003cli\u003ePardo MR, Vilar EG, Mart\u0026iacute;n IS, Mart\u0026iacute;n MA. Bioavailability of magnesium food supplements: A systematic review. Nutrition. 2021 Sep 1;89:111294.\u003c/li\u003e\n \u003cli\u003eIvanovic ND, Radosavljevic B, Zekovic M, Korcok D, Ignjatovic S, Djordjevic B, Milinkovic N. Effects of short-term magnesium supplementation on ionized, total magnesium and other relevant electrolytes levels. Biometals. 2022 Apr;35(2):267-83\u003c/li\u003e\n \u003cli\u003eSalkaya A, Oba S, Altınay M, T\u0026uuml;rk HŞ, Kılın\u0026ccedil; L, Yılmaz A. The effects of perioperative low-dose magnesium sulfate infusion on postoperative pain in lumbar surgery. Signa Vitae. 2024 Jan 1;20(1).\u003c/li\u003e\n \u003cli\u003eRooney MR, Rudser KD, Alonso A, Harnack L, Saenger AK, Lutsey PL. Circulating ionized magnesium: comparisons with circulating total magnesium and the response to magnesium supplementation in a randomized controlled trial. Nutrients. 2020 Jan 20;12(1):263\u003c/li\u003e\n \u003cli\u003ePortincasa P, Bonfrate L, Vacca M, De Angelis M, Farella I, Lanza E, Khalil M, Wang DQ, Sperandio M, Di Ciaula A. Gut microbiota and short chain fatty acids: implications in glucose homeostasis. International journal of molecular sciences. 2022 Jan 20;23(3):1105\u003c/li\u003e\n \u003cli\u003eZhao M, Zhang L, Liu Z. Gut microbiota-mediated pain sensitization: mechanisms and therapeutic implications. Frontiers in Pain Research. 2025 Jul 3;6:1626515\u003c/li\u003e\n \u003cli\u003eCarney SL, Wong NL, Quamme GA, Dirks JH. Effect of magnesium deficiency on renal magnesium and calcium transport in the rat. The Journal of Clinical Investigation. 1980 Jan 1;65(1):180-8.\u003c/li\u003e\n \u003cli\u003eEdinoff AN, Fitz-Gerald JS, Holland KA, Reed JG, Murnane SE, Minter SG, Kaye AJ, Cornett EM, Imani F, Khademi SH, Kaye AM. Adjuvant drugs for peripheral nerve blocks: The role of NMDA antagonists, neostigmine, epinephrine, and sodium bicarbonate. Anesthesiology and Pain Medicine. 2021 Jul 5;11(3):e117146.\u003c/li\u003e\n \u003cli\u003eJin Z, Zhao J. Effectiveness and impact of intravenous magnesium sulfate in spinal surgery systematic review and meta-analysis. Frontiers in Pharmacology. 2025 Jun 18;16:1624119.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Magnesium Oxide, Oral Administration, Pharmacokinetics, Safety, Drug Tolerance","lastPublishedDoi":"10.21203/rs.3.rs-8335012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8335012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMagnesium oxide, though poorly soluble with low bioavailability, is widely used for magnesium supplementation due to its high elemental content and affordability. This study aimed to evaluate the safety, dose-dependent absorption, and pharmacokinetics of oral magnesium oxide at two dosage levels in healthy male volunteers.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA randomized, open-label pharmacokinetic study was conducted in 24 healthy male volunteers aged 18\u0026ndash;45 years, who were equally assigned to receive a single oral dose of either 750 mg or 2000 mg of magnesium oxide. Plasma magnesium concentrations were measured at baseline and multiple time points up to 12 hours post-dose using colorimetric assay. Pharmacokinetic parameters including Cmax, Tmax, AUC, half-life, mean residence time, and clearance were calculated using non-compartmental analysis. Safety was assessed by monitoring vital signs, laboratory parameters, ECG, and adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe study showed saturable, nonlinear absorption kinetics with no proportional increase in Cmax or AUC at the higher dose. Incremental exposure parameters were also comparable between doses, further reinforcing the presence of saturable and nonlinear absorption kinetics. Tmax was significantly shorter in the 2000 mg group (p\u0026thinsp;=\u0026thinsp;0.025). Both doses were well tolerated without serious adverse events or gastrointestinal side effects.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eIn summary, this study demonstrates that oral MgO displays rate differences without proportional exposure gains across 750\u0026ndash;2000 mg, supporting a saturable absorption model with a practical ceiling on systemic delivery. These findings provide a pharmacokinetic rationale for cautious dose escalation and support the feasibility of MgO as a well-tolerated oral option for perioperative magnesium optimization.\u003c/p\u003e","manuscriptTitle":"Randomized, Open-Label Pharmacokinetic Study of Oral Magnesium Oxide in Healthy Volunteers","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-19 14:11:37","doi":"10.21203/rs.3.rs-8335012/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ce735dc8-cb76-45df-9e64-2d37b3fedf85","owner":[],"postedDate":"December 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-07T14:55:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-19 14:11:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8335012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8335012","identity":"rs-8335012","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}