Effect of Modulation of Uridine 5’-Diphospho-Glucuronosyl Transferase 1A Enzymes by Jatropha curcas Extracts on the Pharmacokinetics of Dolutegravir

Effect of Modulation of Uridine 5’-Diphospho-Glucuronosyl Transferase 1A Enzymes by Jatropha curcas Extracts on the Pharmacokinetics of Dolutegravir | 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 Effect of Modulation of Uridine 5’-Diphospho-Glucuronosyl Transferase 1A Enzymes by Jatropha curcas Extracts on the Pharmacokinetics of Dolutegravir Mary Olufunmilayo Ologe, Olalekan Ahmed Yusuf, Olubunmi Atolani, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6232514/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Concomitant herbal medicine and antiretroviral therapy can result in adverse effects or diminished drug efficacy. This study determined the effect of Jatropha curcas on UGT1A activity and its implications on dolutegravir (DTG) pharmacokinetics during concomitant administration. Methods The effects of aqueous (AJC) and ethanol (EJC) extracts of J. curcas were evaluated in rat liver microsomes, and UGT1A activity was determined using spectrophotometric techniques. Eighty Wistar rats were divided into five groups: control group (water ad libitum, then DTG, 10 mg/kg on day 7), AJC pretreatment (PT) group (AJC 200 mg/kg for 7 days + DTG 10 mg/kg on day 7), EJC PT group (EJC 200 mg/kg for 7 days + DTG 10 mg/kg on day 7), AJC co-administration group (CA) (AJC 200 mg/kg + DTG 10 mg/kg for 7 days), and EJC CA group (EJC 200 mg/kg + DTG 10 mg/kg). On day 8, blood samples were collected at different time intervals and plasma concentration of DTG was determined using high liquid chromatography. Results AJC and EJC caused moderate in vitro inhibition of UGT1A activity with IC 50 88.02 ± 3.41 and 79.09 ± 1.03 respectively. Co-administration of AJC and EJC with dolutegravir demonstrated a significant increase in area under the curve concentration (AUC) and maximum plasma concentration of (C max ) of dolutegravir. Conclusion It was observed from the result that the co-administration of AJC and EJC with DTG in Wistar rats, triggered herb-drug interactions. Thus, J. curcas extracts should be used with caution by HIV patients on DTG therapy. Pharmacokinetics Natural Product Chemistry Herbal interaction Alternative medicine Dolutegravir Jatropha curcas Human immunodeficiency virus Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The population in impoverished and developing nations particularly in Africa depends on herbal medicine and their bioactive compounds as a form of supplementary and/or alternative medicine (Okaiyeto & Oguntibeju, 2021 ). Thus, concurrent use of herbal medicine with conventional drug is inevitable, especially in people with chronic diseases such as human immunodeficiency virus (HIV) infection (Ilomuanya et al., 2017 ). This may alter the pharmacological properties of the conventional drug or vice versa in the body (Bernardo J, 2024 ). Jatropha curcas is a plant that is often used for its several ethnomedicinal uses but has been shown in scientific literatures to have antiviral potentials, including anti-HIV activity and has been utilized by HIV-positive individuals in African countries (Utshudi et al., 2022 , Saleh et al., 2023 ). A study reported J. curcas as one of the frequently used plants by traditional healers to treat HIV infection in Nigeria(Njan et al., 2019 ). Studies supporting the use of herbal medicine in the treatment of HIV/AIDS and related opportunistic diseases have been published (Marwa et al., 2024 , Nkechi & Bassi, 2024 ). This could be the reason for the perceived cure among patients that utilize these traditional healers (Mahe et al., 2017 ). Highly active antiretroviral therapy (HAART) is a form of HIV infection treatment strategy that involves the combination of two antiretroviral drugs (ARV) class with one other class of ARVs (Peng et al., 2023 ). These regimens were able to suppress viral replication and transformed this fatal condition into a chronic manageable disease. Six classes of ARVs have been approved for HIV infection treatment, each class targets a step, or enzymes involved in HIV life cycle (Segal-Maurer et al., 2022 ). Dolutegravir (DTG) and cabotegravir belong to the class of ARVs known as Integrase strand inhibitors (INSTIs) (Sivanandy et al., 2023 ). DTG was introduced into Nigeria's healthcare system in 2019 and has since become the first-line antiretroviral regimen for HIV-infected people (NASCP, 2021 ). This drug has been previously reported to be well tolerated, it has favorable pharmacokinetic profile with minimal adverse effects (WHO, 2022 ). However, recent studies have linked DTG to increased reporting of adverse effects, most of which are inflammatory, particularly in female patients (Povar-Echeverría et al., 2021 ). DTG is primarily metabolized by uridine diphosphate glucuronosyltransferases 1A enzymes (UGT1A), responsible for the glucuronidation of DTG to form a pharmacologically inactive DTG glucuronide (Jacobs et al., 2024 ). Since DTG is a substrate for UGT1A enzymes, xenobiotics as well as phytochemicals that modulate UGT1A enzymes can potentially alter DTG pharmacokinetics. This alteration may lead to significant herb-drug interactions (HDIs). Unlike cytochrome P450 enzymes, few studies have reported that inhibition of UGT enzymes by phytochemicals in herbs is responsible for HDIs (Ologe et al., 2024 ). Therefore, parallel use of herbal medicine along with antiretroviral drugs may lead to clinically relevant drug interactions. The effect of herbal medicines on the safety and efficacy of DTG has not been thoroughly investigated. Thus, both in vitro and in vivo animal studies were explored to determine the potential HDIs involving extract of J. curcas leaf and DTG. Materials and Methods Drugs and Reagents Standard DTG, niflumic acid, and Uridine diphosphoglucuronic acid (UDPGA 95%) (> 99%) were purchased from AK Scientific (CA, USA). Triton X-100, p-nitrophenol, ethanol, Dimethyl sulfoxide (DMSO), magnesium chloride, and potassium chloride were purchased from Sigma Aldrich (St. Louis, MA, USA). All other chemicals and solvents were HPLC quality. Milli-Q was utilized to purify deionized water (Millipore, Billerica, MA). Plant Materials J. curcas leaf extracts were extracted at Faculty of Basic Clinical Sciences (Department of Pharmacology and Therapeutics), University of Ilorin, according to the previously published protocol (Rahu et al., 2021 ). Fresh leaves of J. curcas was collected in Malete, Moro Local Government Area, Kwara state, Nigeria, while the voucher specimen was deposited at the Department of Plant Biology, University of Ilorin with reference number UILH001/1030/2024. The dried leaves of J. curcas were weighed (1g) and extracted with water and ethanol respectively. The aqueous extract was filtered using vacuum filtration and muslin cloth, concentrated to dryness, resultant extract was freeze dried and labelled AJC. Also, the ethanol extract was filtered, evaporated to dryness using rotary evaporator and resultant extract was labelled EJC. All the dried extracts were stored in a bottle at 2–4° C. The percentage yield was calculated by dividing the total weight of extracted residue in grams by the total dried matter weight in grams multiply by hundred. HPLC condition An Agilent HPLC system containing a Quat Pump VL G711A and autosampler G7129A equipped with DAD WR G71115A UV detector was used for the determination of DTG concentration. The separation was performed on poroshell column 120 EC-C 18 5µm (4.6 x 250 mm). The mobile phase composition was acetonitrile:water (15:85% v/v), with a flow rate of 0.7 mL/ min, 20 µL injection volume, and detection at 258 nm. Experimental Animals The male Wistar rats, weighing 201–237 g were used for in vitro and in vivo studies to determine the effect of J. curcas leaf extracts on UGT1A activity and dolutegravir pharmacokinetics, respectively. All the rats were given food and water ad libitum . Ethical approval from University of Ilorin ethical review committee (UERC Approval number: UERC/ASN/2021/2292) was obtained for this study. Preparation of Rat liver microsomes. Rat liver microsomes (RLMs) were prepared as previously described with slight modifications (Agbenyeku et al., 2022 ). Six rats were anesthetized with injection ketamine/xylazine 0.6 mL/0.2 kg before the surgery. After the anesthesia took effect, rats’ abdomen was incised to expose the abdominal cavity. The liver was perfused in situ with 10 mL ice-cold potassium phosphate buffer saline (pH 7.4) and the liver was taken out. The liver was dried using a tissue and weighed, ice-cold sucrose (0.25 M) containing 10 mM Tris-HCl at pH 7.4 (three times of the weight) was added to the isolated liver and homogenized in a homogenizer (Potter-Elvehjem, USA) at 4 ° C. The homogenates were then pooled in a glass beaker. Afterwards, the homogenate was filled into micro-centrifuge tubes and centrifuged for 5 minutes at 600 x g followed by another 10 minutes at 12,000 x g in a refrigerated centrifuge (Eppendorf, Germany) to obtain a post-mitochondrial supernatant. The supernatant was removed, mixed with CaCl 2 and centrifuged for 20 minutes (-4°C) at 20,000 x g to obtain pellets. The pellet was suspended in a mixture of 150 mM KCl and 10 mM Tris–HCl and centrifuged for 20 minutes (-4°C) at 20,000 × g to obtain a pink-colored microsomal pellet. Lastly, the microsomal pellet was suspended in 0.5 ml of 0.1 M potassium phosphate buffer containing 20% glycerol and stored at − 80° C until needed for the in vitro study. The microsomes obtained were further characterized by determining their protein concentration. UGT assay using rat liver microsomes The UGT1A activity was performed as previously described with slight modification (Purwantiningsih et al., 2019 ). Preparation of the standard curve for p-nitrophenol To prepare a standard curve for p-nitrophenol, 5 mM of stock solution was dissolved in distilled water. In a separate test tube, a serial dilution was made from the stock solution at concentrations ranging from 0.2 to 1 mM. To each of the test tube, 25 µl of 1-M Tris-HCl (pH 7.4) and 50 mM MgCl 2 were added. After 5 minutes of preincubation at 37 ° C, then 25 µl of 30 mM UDPGA was added to initiate the reaction. In the blank group, p-nitrophenol was replaced with distilled water (200 µl) and each set of reading was made in triplicate (n = 3). After 15 minutes of incubation at 37ºC, the reaction was terminated by adding 1 ml of ice-cooled trichloroacetic acid (5%). After centrifugation, the supernatant was removed, and 50 µl of 5 M NaOH was added to adjust the color. The mixture was then incubated for 10 minutes at room temperature. The absorbance was measured, and a standard curve was plotted. In vitro effect of J. curcas leaf extract on UGT activity using rat liver microsomes. The reactions were performed using rat liver microsomes. The reaction mixture containing p-nitrophenol (5 mM, 25 µL), with or without niflumic acid (100 µM) and either of the J. curcas extracts (AJC or EJC), Tris-HCl (1 M, pH 7.4), Triton X-100 (0.25% w/v), and MgCl 2 (50 mM) and 50 µL of microsomes (1.88 mg/mL), were preincubated in a water-bath shaker at 37 ° C for 5 minutes. After, a volume of 25 µL of 30 mM UDPGA was added to initiate the reaction, followed by incubation at 37°C for 15 minutes and the reactions were terminated by adding 1 mL of 5% ice-cooled trichloroacetic acid. The samples were centrifuged for 5 minutes at 4,000 x g at room temperature. Then, 200 µL of the supernatant was removed and 50 µL of 5 M NaOH was added to adjust the color. The mixture was then incubated for 10 minutes at room temperature. Afterwards, the absorbance was measured at 410 nm. The amount of p-nitrophenol consumed during the glucuronidation reaction was determined from the sample absorbance by using the standard curve for p-nitrophenol. The UGT enzyme activity was calculated based on the p-nitrophenol consumed in the glucuronidation reaction (Eq. 1). The time of incubation was 15 minutes, and the final protein concentration was 0.38 mg/mL. The assay expressed the UGT activity as nmol p-nitrophenol consumed/min/mg protein, then was calculated to get the percentage activity. Evaluation of the In vivo effect of J. curcas on the Pharmacokinetics of Dolutegravir Pharmacokinetics study design Eighty male Wistar rats were used for this study. To determine the sample size, an assumption of a coefficient variation (% CV) due to biological variability < 20% between each treatment arm and the control group was used. For each group a minimum power of 80% to detect changes in pharmacokinetic (PK) data was assumed with statistical power of p < 0.05. Thus, a minimum of four animals per group (n = 4) is required, and sixteen rats for each group to allow adequate blood sampling, giving a total of 80 rats. The rats were housed under a 12 h light/dark cycle with free access to food and potable water for at least seven days to allow them to acclimatize before use. The rats were randomly divided into five groups of sixteen rats each i.e. control, AJC pretreatment (AJC PT), EJC pretreatment (EJC PT), AJC coadministration (AJC CA), and EJC coadministration (EJC CA) groups. The control group received distilled water alone for 7 days; AJC PT group received 200 mg/kg of aqueous J. curcas extract alone for 7 days, followed by administration of 10 mg/kg DTG on day 7; EJC PT group received 200 mg/kg of ethanol extract of J. curcas alone for 7 days, followed by administration of 10 mg/kg DTG on day 7; AJC CA group received 200 mg/kg aqueous extract of J. curcas along with 10 mg/kg DTG for 7 days; and EJC CA group received 200 mg/kg ethanol extract of J. curcas along with 10 mg/kg DTG for 7 days. After drug administration, each group was further subdivided into two groups of four rats, such that only two blood samples per time interval (0.5, 1, 2, 4, 6, 8, 12, and 24) were collected from individual animal within 24 h from the retro-orbital plexus under injection ketamine anesthesia. Plasma was obtained by centrifugation at 3000 g for 10 minutes and stored at -20 ° C until HPLC analysis. HPLC Analysis A stock solution of DTG was prepared in methanol such that the final concentration was 100 mg/L. The stock solutions were stored at 20°C until they were used for analysis. The stock solutions were diluted and spiked in plasma appropriately to make plasma calibration standard ranging 0.05-1mg/L for DTG. Plasma concentrations of DTG were determined using a previously validated HPLC method (Yarlagadda et al., 2023 ). For plasma preparation, 200 µL cold acetonitrile was added to 500 µL of plasma calibration standard and test sample. The samples were vortexed for 2 minutes, followed by centrifugation at 1500 g for 5 minutes at room temperature. The resulting supernatants were transferred to a prelabeled tube and evaporated to dryness under nitrogen at 40 ° C. The dried residues were dissolved in 200 µL acetonitrile, vortexed thoroughly and then 20 µL was injected for analysis. Data analysis The in vitro studies data were expressed as mean ± SEM of triplicate samples (n-3). One-way analysis of variance (ANOVA) was used to compare the effects of different concentrations of AJC and EJC with the positive control (PC) on UGT enzymes activity. Statistical analysis was performed using GraphPad Prism version 9.5.0 software (San Diego, CA, USA). IC 50 value and non-linear regression analysis were performed using GraphPad Prism 9.5.0. P < 0.05 was considered statistically significant. The in vivo data was analyzed based on a non-compartmental pharmacokinetic model using PKanalix 2024 version (Lixoft, France), pharmacokinetics fitting software to calculate the model-independent pharmacokinetic parameters. The parameters determined were area under the plasma concentration-time curve (AUC), apparent clearance (CL/f), apparent volume of distribution (Vd/f), peak concentration (T max ), maximum concentration (C max ), and elimination constant (K el ). The pharmacokinetic parameters were compared between the five groups using a paired two samples t-test and a two-tailed significance level of p ≤ 0.05 (GraphPad Prism 9.5.0 San Diego, CA, USA). Results Potential inhibition of UGT activity was analyzed using aqueous and ethanol extracts of J. curcas at 1000 µg/mL; niflumic acid (NFA) 100 µM was used as positive control since this drug is a known inhibitor of UGT1A enzyme activity. The UGT-mediated reaction was performed in rat liver microsomes to evaluate the effect of AJC and EJC on p-nitrophenol glucuronide formation. NFA significantly (p < 0.0001) inhibited enzymatic consumption of p-nitrophenol when compared with the control (Fig. 1 ), indicating the proper performance of this inhibitor under the established reaction conditions. Furthermore, EJC exhibited the highest inhibitory effect on UGT1A activity when compared to the remaining groups. As shown in Figs. 2 and 3 , AJC and EJC substantially inhibited UGT1A activity. The AJC and EJC showed highest UGT inhibitory activity at 250 µg/mL when compared to NFA (Figs. 2 and 3 ). However, the enzyme inhibitory effect of EJC was dose-dependent up to 250 mg/ml, the enzyme inhibitory effect increased as the extract concentration increased (Fig. 3 ). HPLC-UV analysis was carried out to quantify the amount of DTG in the rat plasma. The maximum plasma concentration of dolutegravir (C max ) was increased for AJC PT, EJC PT, AJC CA, and EJC CA group (0.0034, 0.0026, 0.0034, and 0.0047 mg/L respectively) compared to the control group (0.0015 mg/L). The C max for EJC CA group was highest (0.047 mg/mL) compared to the other groups. The T max values for the control, pre-treatment, and co-administration groups were between 0.5–1 h (Fig. 4 ). The non compartmental analysis of single dose DTG result showed that area under the plasma concentration-time curve from time zero extrapolated to 24 h (AUC 0 − 24 ) for AJC PT, EJC PT, AJC CA, and EJC CA were 0.04, 0.025, 0.02, and 0.03 mg.h./L respectively, slightly higher than that of control group 0.023 mg.h./L (Table 1 ). Table 1 Comparative effect of J. curcas (200 mg/kg) on the pharmacokinetic parameters of single oral dose of dolutegravir. Parameters Control AJC PT EJC PT AJC CA EJC CA AUC 0 − 24 0.023 0.04 0.025 0.002 0.03 C max 0.0015 0.0034 * 0.0026 * 0.0034 * 0.0047 * T max 0.5 0.5 0.5 1 1 K el 0.092 0.021 0.15 0.43 0.43 CL/f 381.33 89.63 392.77 488.54 488.54 V d /f 4161.43 4251.08 2593.2 1142.57 1142.57 AUMC 35.49 91.94 9.78 0.071 9.44 MRT 12.28 49.54 8.11 4.63 6.04 Mean ± SEM, n = 4 and *p < 0.05. DTG - dolutegravir (10mg/kg, p.o), AJC PT- aqueous J. curcas extract pretreatment group, EJC PT- ethanol J. curcas extract pretreatment group, AJC- CA aqueous J. curcas extract coadministration group, EJC CA- ethanol J. curcas extract coadministration group. AUC 0 − 24 - area under the concentration-time curve (mg.h/L), C max - maximum plasma concentration (mg/mL), T max - time to reach maximum temperature (h); K el - elimination constant; CL/f- apparent clearance (L/h); V d/f - apparent volume of distribution (L/kg); AUMC- total area under the first moment curve; MRT- mean residence time. Discussion The screening of herbal medicines for possible herb-drug interactions has gained prominence due to the upsurge in the use of herbal medicines along with the orthodox drugs (Pan et al., 2022 ). The risk of HDIs among HIV patients is higher due to the multiple drugs used in the management of HIV infection and associated opportunistic infections (Thomford et al., 2016 ). Thus, evaluating herbal extracts for possible HDIs is extremely urgent for antiretroviral drugs. Herb-drug interactions in which herbal medicine is a “perpetrator” could lead to treatment failure or adverse reactions (Olawoye et al., 2017 ). However, some HDIs may be beneficial; for instance, herbal medicines that increase orthodox drug absorption and bioavailability may increase their efficacy (Lam et al., 2020 ). The notable mechanisms of HDIs include modulation of CYP450, UGT, and drug transporters (Jeong et al., 2015 ). The inhibition of drug metabolism involving cytochrome P450 enzymes is the most studied, however, there are fewer studies on inhibition of UGT as a mechanism of herb-drug interactions (Detampel et al., 2012 ). The concentration dependent inhibition of UGT activity by the aqueous and ethanol extracts of J. curcas is in tandem with some reported moderate inhibition of UGT by some other medicinal plants. Liu et al. reported 53 natural and synthetic flavonoids that are potent inhibitors of UGT enzyme activity (Liu et al., 2019 ). Thus, findings from this study agree with previous studies on the inhibitory effect of medicinal plant extracts on UGT activity. Concurrent consumption of J. curcas leaves with drugs that are substrates of UGT enzymes, such as DTG; could increase their plasma concentrations that can lead to adverse effects and HDI. The in vivo experiment was performed based on the principle that the inhibition of major enzymes UGT1A1 responsible for the metabolism of DTG will lead to an increase in the plasma concentration of DTG when orally administered. Adult male rats were used for this study because of their lower hormonal, body weight, organ size, and metabolic rate variability (Kim et al., 2014 ). There are several reports of ethnomedicinal use of J. curcas ; this plant contains phytochemicals that are responsible for its pharmacological activities as well as toxic compounds such as phorbol esters (Leyva-Padrón et al., 2020 ). Thus, there is possibility that its consumption with DTG may have clinically relevant herb-drug interactions. The T max range for this study correlates with the reported T max for DTG (Cottrell et al., 2013 ). The C max of DTG increased significantly in the J. curcas extract-treated group, indicating increased absorption and bioavailability of the drug. The area under the plasma concentrations curve (AUC) of DTG was also increased in all the extract-treated groups. The AUC and C max are used to measure the extent of drug bioavailability, which is impacted by the first pass effect (Nduka et al., 2017 ). The AUC, AUMC, Cmax, and MRT that were elevated in the AJC pre-treatment group indicates increased systemic bioavailability of DTG and possible inhibition of UGT which is the enzyme responsible for the metabolism of DTG in the liver. Therefore, concomitant use of J. curcas extracts by patient on DTG therapy may be harmful due to the inhibition of UGT enzymes. This observed interaction between DTG and extracts of J. curcas leaf may lead to poor adherence, treatment failure, poor patient safety and clinical outcomes. This finding on aqueous extract is important because water extraction is the commonest method of J. curcas extract preparation (Dangambo et al., 2015 ). Only AUC and C max were increased in the ethanolic extracts of J. curcas for the pre-treatment and co-administration group indicating possible reduced first past effect. Conclusion In conclusion, J. curcas leaf extracts inhibit UGT enzymes activity. This explains the altered DTG pharmacokinetics seen in rats treated with J. curcas leaf extracts. The increase in AUC and C max of DTG in aqueous and ethanol extracts of J. curcas leaf indicates in vivo inhibition of UGT. Thus, aqueous and ethanol extracts of J. curcas leaf could cause herb-drug interactions when co-administered with DTG in Wistar rats. It is therefore recommended that HIV patients on DTG therapy should exercise caution when using extracts of J. curcas . Declarations Acknowledgements: All authors acknowledge the Tertiary Education Trust Fund (TETFUND) for funding this research. Author contributions M.O. Ologe: supervised the conducted research, contributed to the research methodology, data analysis, paper writing, revision, and submission; O.A. Yusuf: Conducted research, data analysis, performed the statistical analysis, paper writing, primarily responsible for final content and submission; O. Atolani: co-supervised the conducted research, contributed to the research methodology, data analysis, paper writing, revision, and submission; A.A. Njan: supervision, validation, and participated in paper writing; A.C. Tella: supervision, validation, provided essential reagents and materials and participated in paper writing. The first draft of the manuscript was written by O.A. Yusuf and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding: Funding was received for this study from Tertiary Education Trust Fund (TETFUND) for Institution-Based Intervention Grant (IBR) with award number: TETF/DR&D/CE/UNT/AZARE IBR/2023/VOL1. Data availability The datasets analyzed during the current study are available from the corresponding author on reasonable request. Competing interests , No competing interest declared by the authors. Research involving human and animal participants This study does not contain any studies on human subjects performed by any of the authors. All animal procedures were performed according to the ethical standards of the University of Ilorin ethical research committee, with approval number UERC/ASN/2021/2292. References Agbenyeku, M. A., Appiah-Opong, R., Obese, E., Biney, R. P., Adakudugu, E. A., Forkuo, A. D., Osei, S. A., Abeka, M. K., & Ameyaw, E. O. (2022). Effect of Xylopic Acid on Cytochrome P450 Enzymes . https://doi.org/10.1155/2022/4524877 Bernardo J, V. P. (2024). Herb-drug interactions: A short review on central and peripheral nervous system drugs. Phytother Res. , 38 (4), 1903–1931. Cottrell, M.L., Hadzic, T. & Kashuba, A. D. M. (2013). 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African herbal medicines: Adverse effects and cytotoxic potentials with different therapeutic applications. In International Journal of Environmental Research and Public Health (Vol. 18, Issue 11, p. 5988). https://doi.org/10.3390/ijerph18115988 Olawoye, O., Adeagbo, B., & Bolaji, O. (2017). Effects of Moringa oleifera Leaf Powder Suspension on the Pharmacokinetics of Amodiaquine in Rats. Journal of Complementary and Alternative Medical Research , 3 (4), 1–8. https://doi.org/10.9734/jocamr/2017/35960 Ologe, M. O., Yusuf, O. A., Adepiti, A. O., Atolani, O., Njan, A. A., Tella, A. C., & Iwalewa, E. O. (2024). Pharmacokinetics-Based Herb-Drug Interactions: Current Status in Experimental Models in Nigeria. Acta Facultatis Medicae Naissensis , 41 (4), 465–489. https://doi.org/10.5937/afmnai41-47333 Pan, H., Wu, L., Wang, P., Chiu, P., & Wang, M. (2022). Real-world evidence of the herb-drug interactions . 30 (3). Peng, Y., Zong, Y., Wang, D., Chen, J., Chen, Z.-S., Peng, F., & Liu, Z. (2023). Current drugs for HIV-1: from challenges to potential in HIV/ AIDS . https://doi.org/10.3389/fphar.2023.1294966 Povar-Echeverría, M., Comet-Bernad, M., Gasso-Sánchez, A., Ger-Buil, A., Navarro-Aznarez, H., Martínez-Álvarez, R., & Arazo-Garcés, P. (2021). Neuropsychiatric adverse effects of dolutegravir in real-life clinical practice. Enfermedades Infecciosas y Microbiologia Clinica (English Ed.) , 39 (2), 78–82. https://doi.org/10.1016/J.EIMCE.2020.02.009 Purwantiningsih, P., Hussin, A. H., Ismail, S., & Chan, K. L. (2019). In vitro and in vivo effect of eurycoma longifolia root extract on UDP-glucuronosyltransferase activity. Journal of Applied Pharmaceutical Science , 9 (9), 077–083. https://doi.org/10.7324/JAPS.2019.90911 Rahu, M. I., Naqvi, S. H. A., Memon, N. H., Idrees, M., Kandhro, F., Pathan, N. L., Sarker, M. N. I., & Aqeel Bhutto, M. (2021). Determination of antimicrobial and phytochemical compounds of Jatropha curcas plant. Saudi Journal of Biological Sciences , 28 (5), 2867–2876. https://doi.org/10.1016/J.SJBS.2021.02.019 Saleh, Z. M., Abdel Azeiz, A. Z., Mehany, A. B. M., & El-Swaify, Z. A. S. (2023). Anticancer and Antimicrobial Activity of Jatropha’s Leaves Extracts. Egyptian Journal of Botany , 63 (2), 621–634. https://doi.org/10.21608/ejbo.2023.162736.2137 Segal-Maurer, S., DeJesus, E., Stellbrink, H.-J., Castagna, A., Richmond, G. J., Sinclair, G. I., Siripassorn, K., Ruane, P. J., Berhe, M., Wang, H., Margot, N. A., Dvory-Sobol, H., Hyland, R. H., Brainard, D. M., Rhee, M. S., Baeten, J. M., & Molina, J.-M. (2022). Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. New England Journal of Medicine , 386 (19), 1793–1803. https://doi.org/10.1056/nejmoa2115542 Sivanandy, P., Ng Yujie, J., Chandirasekaran, K., Hong Seng, O., & Azhari Wasi, N. A. (2023). Efficacy and Safety of Two-Drug Regimens That Are Approved from 2018 to 2022 for the Treatment of Human Immunodeficiency Virus (HIV) Disease and Its Opportunistic Infections. In Microorganisms (Vol. 11, Issue 6). https://doi.org/10.3390/microorganisms11061451 Thomford, N. E., Awortwe, C., Dzobo, K., Adu, F., Chopera, D., Wonkam, A., Skelton, M., Blackhurst, D., & Dandara, C. (2016). Inhibition of CYP2B6 by medicinal plant extracts: Implication for use of efavirenz and nevirapine based highly active anti-retroviral therapy (HAART) in resource-limited settings. Molecules , 21 (2), 211. https://doi.org/10.3390/molecules21020211 Utshudi, A. L., Oleko, R. O., Kayembe, C. T., Onautshu, D. O., Kitete, E. M., Mbala, B. M., & Mpiana, P. T. (2022). Antiviral Activities of Jatropha curcas: A Review. International Journal of Pathogen Research , 9 (3), 33–46. https://doi.org/10.9734/ijpr/2022/v9i330228 WHO. (2022). Update on the Transition to Dolutegravir-Based Antiretroviral Therapy Report of a WHO Meeting, 29-30 March 2022 . March . Yarlagadda, D. L., Nayak, A. M., Brahmam, B., & Bhat, K. (2023). Exploring the Solubility and Bioavailability of Sodium Salt and Its Free Acid Solid Dispersions of Dolutegravir. Advances in Pharmacological and Pharmaceutical Sciences , 2023 . https://doi.org/10.1155/2023/7198674 Additional Declarations The authors declare no competing interests. Supplementary Files GraphicalAbstract.png Graphic Abstract Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6232514","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":429183209,"identity":"7d5f18cf-7924-4f84-935e-aadc26554542","order_by":0,"name":"Mary Olufunmilayo Ologe","email":"","orcid":"https://orcid.org/0000-0001-5406-2213","institution":"University of Ilorin, Kwara State, Nigeria","correspondingAuthor":false,"prefix":"","firstName":"Mary","middleName":"Olufunmilayo","lastName":"Ologe","suffix":""},{"id":429183210,"identity":"3fa486d2-544c-487d-8273-2297b2595f3a","order_by":1,"name":"Olalekan Ahmed Yusuf","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-7797-7173","institution":"Federal University of Health Sciences Azare, Bauchi State, Nigeria","correspondingAuthor":true,"prefix":"","firstName":"Olalekan","middleName":"Ahmed","lastName":"Yusuf","suffix":""},{"id":429183211,"identity":"da80b391-dd38-4ecd-8cc2-bb7b34689e19","order_by":2,"name":"Olubunmi Atolani","email":"","orcid":"","institution":"University of Ilorin, Kwara State, Nigeria","correspondingAuthor":false,"prefix":"","firstName":"Olubunmi","middleName":"","lastName":"Atolani","suffix":""},{"id":429183212,"identity":"93669820-26a1-4983-93e3-cbfd2238f03e","order_by":3,"name":"Anoka Ayembe Njan","email":"","orcid":"","institution":"University of Ilorin, Kwara State Nigeria","correspondingAuthor":false,"prefix":"","firstName":"Anoka","middleName":"Ayembe","lastName":"Njan","suffix":""},{"id":429183213,"identity":"3c29d302-cdcc-4ca8-8b80-22e194fba27f","order_by":4,"name":"Adedibu Clement Tella","email":"","orcid":"","institution":"University of Ilorin, Kwara State Nigeria","correspondingAuthor":false,"prefix":"","firstName":"Adedibu","middleName":"Clement","lastName":"Tella","suffix":""}],"badges":[],"createdAt":"2025-03-15 11:25:05","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-6232514/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6232514/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78734476,"identity":"cc7170ab-e1b5-4e40-8f21-84dd4e197f42","added_by":"auto","created_at":"2025-03-18 08:00:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14046,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of \u003cem\u003eJ. curcas\u003c/em\u003e on UGT activity in rat liver microsomes.\u003c/p\u003e\n\u003cp\u003eMean ± SEM (n=3) ****P\u0026lt;0.0001 compared to the control. AJC- aqueous extract of \u003cem\u003eJ. curcas\u003c/em\u003e leaf, EJC- ethanol extract of \u003cem\u003eJ. curcas\u003c/em\u003e leaf, NFA- Niflumic acid, known UGT1A inhibitor.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6232514/v1/9f783440793965cf4b1f2324.png"},{"id":78735424,"identity":"8cac15a0-2012-4995-873d-115172a82fe9","added_by":"auto","created_at":"2025-03-18 08:08:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":19123,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of different concentrations of aqueous \u003cem\u003eJ. curcas\u003c/em\u003e extracts on UGT activity in rat liver microsomes. Mean ± SEM (n=3), **P \u0026lt; 0.01, ***P\u0026lt;0.001, and ****P \u0026lt; 0.0001. NFA- niflumic acid, AJC-aqueous extract of \u003cem\u003eJ. curcas\u003c/em\u003e leaf, UGT-uridine diphosphoglucuronosyl transferase.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6232514/v1/aeae401ee512bbddedd968cd.png"},{"id":78735452,"identity":"fe7e6c4c-fad3-461d-952f-e36f4cfbfafa","added_by":"auto","created_at":"2025-03-18 08:08:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19283,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of different concentrations of ethanol \u003cem\u003eJ. curcas\u003c/em\u003e extracts on UGT activity in rat liver microsomes. Mean ± SEM (n=3), **P \u0026lt; 0.01 and ****P \u0026lt; 0.0001. NFA- niflumic acid, EJC-aqueous extract of \u003cem\u003eJ.\u003c/em\u003e \u003cem\u003ecurcas\u003c/em\u003e leaf, UGT-uridine diphosphoglucuronosyl transferase.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6232514/v1/1bd8ac8798ac5b6eb25ffd52.png"},{"id":78734481,"identity":"1effed5c-ebc2-4d69-921e-c8009dc75891","added_by":"auto","created_at":"2025-03-18 08:00:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":93866,"visible":true,"origin":"","legend":"\u003cp\u003eMean plasma concentration-time profiles of Dolutegravir (DTG) after oral administration of DTG to rats in the presence of AJC or EJC. Mean±SEM; n=4. ID1- DTG alone (control) group, ID2- AJC PT (pretreatment) group, ID3- EJC PT (pretreatment) group, ID4- AJC CA (coadministration) group, and ID5- EJC CA (coadministration) group. AJC and EJC- aqueous and ethanol extracts of \u003cem\u003eJ.curcas\u003c/em\u003e leaf respectively.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6232514/v1/f5db511a69096de67adef4ca.png"},{"id":78736164,"identity":"25beaab2-0dec-4e0a-a6e9-dc56364cf509","added_by":"auto","created_at":"2025-03-18 08:16:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":698258,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6232514/v1/b9aa78d1-5a3e-48b5-a238-df919c709f91.pdf"},{"id":78734479,"identity":"164a712f-1d98-471c-8d5b-45c5bca34956","added_by":"auto","created_at":"2025-03-18 08:00:40","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46855,"visible":true,"origin":"","legend":"\u003cp\u003eGraphic Abstract\u003c/p\u003e","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-6232514/v1/ac707c8a49425ec12596bfb2.png"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eEffect of Modulation of Uridine 5’-Diphospho-Glucuronosyl Transferase 1A Enzymes by Jatropha curcas Extracts on the Pharmacokinetics of Dolutegravir\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe population in impoverished and developing nations particularly in Africa depends on herbal medicine and their bioactive compounds as a form of supplementary and/or alternative medicine (Okaiyeto \u0026amp; Oguntibeju, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Thus, concurrent use of herbal medicine with conventional drug is inevitable, especially in people with chronic diseases such as human immunodeficiency virus (HIV) infection (Ilomuanya et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). This may alter the pharmacological properties of the conventional drug or \u003cem\u003evice versa\u003c/em\u003e in the body (Bernardo J, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). \u003cem\u003eJatropha curcas\u003c/em\u003e is a plant that is often used for its several ethnomedicinal uses but has been shown in scientific literatures to have antiviral potentials, including anti-HIV activity and has been utilized by HIV-positive individuals in African countries (Utshudi et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Saleh et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). A study reported \u003cem\u003eJ. curcas\u003c/em\u003e as one of the frequently used plants by traditional healers to treat HIV infection in Nigeria(Njan et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Studies supporting the use of herbal medicine in the treatment of HIV/AIDS and related opportunistic diseases have been published (Marwa et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2024\u003c/span\u003e, Nkechi \u0026amp; Bassi, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). This could be the reason for the perceived cure among patients that utilize these traditional healers (Mahe et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHighly active antiretroviral therapy (HAART) is a form of HIV infection treatment strategy that involves the combination of two antiretroviral drugs (ARV) class with one other class of ARVs (Peng et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). These regimens were able to suppress viral replication and transformed this fatal condition into a chronic manageable disease. Six classes of ARVs have been approved for HIV infection treatment, each class targets a step, or enzymes involved in HIV life cycle (Segal-Maurer et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Dolutegravir (DTG) and cabotegravir belong to the class of ARVs known as Integrase strand inhibitors (INSTIs) (Sivanandy et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). DTG was introduced into Nigeria's healthcare system in 2019 and has since become the first-line antiretroviral regimen for HIV-infected people (NASCP, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). This drug has been previously reported to be well tolerated, it has favorable pharmacokinetic profile with minimal adverse effects (WHO, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). However, recent studies have linked DTG to increased reporting of adverse effects, most of which are inflammatory, particularly in female patients (Povar-Echeverr\u0026iacute;a et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDTG is primarily metabolized by uridine diphosphate glucuronosyltransferases 1A enzymes (UGT1A), responsible for the glucuronidation of DTG to form a pharmacologically inactive DTG glucuronide (Jacobs et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Since DTG is a substrate for UGT1A enzymes, xenobiotics as well as phytochemicals that modulate UGT1A enzymes can potentially alter DTG pharmacokinetics. This alteration may lead to significant herb-drug interactions (HDIs). Unlike cytochrome P450 enzymes, few studies have reported that inhibition of UGT enzymes by phytochemicals in herbs is responsible for HDIs (Ologe et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Therefore, parallel use of herbal medicine along with antiretroviral drugs may lead to clinically relevant drug interactions. The effect of herbal medicines on the safety and efficacy of DTG has not been thoroughly investigated. Thus, both \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e animal studies were explored to determine the potential HDIs involving extract of \u003cem\u003eJ. curcas\u003c/em\u003e leaf and DTG.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eDrugs and Reagents\u003c/p\u003e \u003cp\u003eStandard DTG, niflumic acid, and Uridine diphosphoglucuronic acid (UDPGA 95%) (\u0026gt;\u0026thinsp;99%) were purchased from AK Scientific (CA, USA). Triton X-100, p-nitrophenol, ethanol, Dimethyl sulfoxide (DMSO), magnesium chloride, and potassium chloride were purchased from Sigma Aldrich (St. Louis, MA, USA). All other chemicals and solvents were HPLC quality. Milli-Q was utilized to purify deionized water (Millipore, Billerica, MA).\u003c/p\u003e \u003cp\u003ePlant Materials\u003c/p\u003e \u003cp\u003e\u003cem\u003eJ. curcas\u003c/em\u003e leaf extracts were extracted at Faculty of Basic Clinical Sciences (Department of Pharmacology and Therapeutics), University of Ilorin, according to the previously published protocol (Rahu et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Fresh leaves of \u003cem\u003eJ. curcas\u003c/em\u003e was collected in Malete, Moro Local Government Area, Kwara state, Nigeria, while the voucher specimen was deposited at the Department of Plant Biology, University of Ilorin with reference number UILH001/1030/2024. The dried leaves of \u003cem\u003eJ. curcas\u003c/em\u003e were weighed (1g) and extracted with water and ethanol respectively. The aqueous extract was filtered using vacuum filtration and muslin cloth, concentrated to dryness, resultant extract was freeze dried and labelled AJC. Also, the ethanol extract was filtered, evaporated to dryness using rotary evaporator and resultant extract was labelled EJC. All the dried extracts were stored in a bottle at 2\u0026ndash;4\u0026deg; C. The percentage yield was calculated by dividing the total weight of extracted residue in grams by the total dried matter weight in grams multiply by hundred.\u003c/p\u003e \u003cp\u003eHPLC condition\u003c/p\u003e \u003cp\u003eAn Agilent HPLC system containing a Quat Pump VL G711A and autosampler G7129A equipped with DAD WR G71115A UV detector was used for the determination of DTG concentration. The separation was performed on poroshell column 120 EC-C 18 5\u0026micro;m (4.6 x 250 mm). The mobile phase composition was acetonitrile:water (15:85% v/v), with a flow rate of 0.7 mL/ min, 20 \u0026micro;L injection volume, and detection at 258 nm.\u003c/p\u003e \u003cp\u003eExperimental Animals\u003c/p\u003e \u003cp\u003eThe male Wistar rats, weighing 201\u0026ndash;237 g were used for \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e studies to determine the effect of \u003cem\u003eJ. curcas\u003c/em\u003e leaf extracts on UGT1A activity and dolutegravir pharmacokinetics, respectively. All the rats were given food and water \u003cem\u003ead libitum\u003c/em\u003e. Ethical approval from University of Ilorin ethical review committee (UERC Approval number: UERC/ASN/2021/2292) was obtained for this study.\u003c/p\u003e \u003cp\u003ePreparation of Rat liver microsomes.\u003c/p\u003e \u003cp\u003eRat liver microsomes (RLMs) were prepared as previously described with slight modifications (Agbenyeku et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Six rats were anesthetized with injection ketamine/xylazine 0.6 mL/0.2 kg before the surgery. After the anesthesia took effect, rats\u0026rsquo; abdomen was incised to expose the abdominal cavity. The liver was perfused \u003cem\u003ein situ\u003c/em\u003e with 10 mL ice-cold potassium phosphate buffer saline (pH 7.4) and the liver was taken out. The liver was dried using a tissue and weighed, ice-cold sucrose (0.25 M) containing 10 mM Tris-HCl at pH 7.4 (three times of the weight) was added to the isolated liver and homogenized in a homogenizer (Potter-Elvehjem, USA) at 4\u003csup\u003e\u0026deg;\u003c/sup\u003eC. The homogenates were then pooled in a glass beaker. Afterwards, the homogenate was filled into micro-centrifuge tubes and centrifuged for 5 minutes at 600 x g followed by another 10 minutes at 12,000 x g in a refrigerated centrifuge (Eppendorf, Germany) to obtain a post-mitochondrial supernatant. The supernatant was removed, mixed with CaCl\u003csub\u003e2\u003c/sub\u003e and centrifuged for 20 minutes (-4\u0026deg;C) at 20,000 x g to obtain pellets. The pellet was suspended in a mixture of 150 mM KCl and 10 mM Tris\u0026ndash;HCl and centrifuged for 20 minutes (-4\u0026deg;C) at 20,000 \u0026times; g to obtain a pink-colored microsomal pellet. Lastly, the microsomal pellet was suspended in 0.5 ml of 0.1 M potassium phosphate buffer containing 20% glycerol and stored at \u0026minus;\u0026thinsp;80\u0026deg; C until needed for the \u003cem\u003ein vitro\u003c/em\u003e study. The microsomes obtained were further characterized by determining their protein concentration.\u003c/p\u003e \u003cp\u003eUGT assay using rat liver microsomes\u003c/p\u003e \u003cp\u003eThe UGT1A activity was performed as previously described with slight modification (Purwantiningsih et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePreparation of the standard curve for p-nitrophenol\u003c/p\u003e \u003cp\u003eTo prepare a standard curve for p-nitrophenol, 5 mM of stock solution was dissolved in distilled water. In a separate test tube, a serial dilution was made from the stock solution at concentrations ranging from 0.2 to 1 mM. To each of the test tube, 25 \u0026micro;l of 1-M Tris-HCl (pH 7.4) and 50 mM MgCl\u003csub\u003e2\u003c/sub\u003e were added. After 5 minutes of preincubation at 37\u003csup\u003e\u0026deg;\u003c/sup\u003eC, then 25 \u0026micro;l of 30 mM UDPGA was added to initiate the reaction. In the blank group, p-nitrophenol was replaced with distilled water (200 \u0026micro;l) and each set of reading was made in triplicate (n\u0026thinsp;=\u0026thinsp;3). After 15 minutes of incubation at 37\u0026ordm;C, the reaction was terminated by adding 1 ml of ice-cooled trichloroacetic acid (5%). After centrifugation, the supernatant was removed, and 50 \u0026micro;l of 5 M NaOH was added to adjust the color. The mixture was then incubated for 10 minutes at room temperature. The absorbance was measured, and a standard curve was plotted.\u003c/p\u003e \u003cp\u003e \u003cem\u003eIn vitro\u003c/em\u003e effect of \u003cem\u003eJ. curcas\u003c/em\u003e leaf extract on UGT activity using rat liver microsomes.\u003c/p\u003e \u003cp\u003eThe reactions were performed using rat liver microsomes. The reaction mixture containing p-nitrophenol (5 mM, 25 \u0026micro;L), with or without niflumic acid (100 \u0026micro;M) and either of the \u003cem\u003eJ. curcas\u003c/em\u003e extracts (AJC or EJC), Tris-HCl (1 M, pH 7.4), Triton X-100 (0.25% w/v), and MgCl\u003csub\u003e2\u003c/sub\u003e (50 mM) and 50 \u0026micro;L of microsomes (1.88 mg/mL), were preincubated in a water-bath shaker at 37\u003csup\u003e\u0026deg;\u003c/sup\u003eC for 5 minutes. After, a volume of 25 \u0026micro;L of 30 mM UDPGA was added to initiate the reaction, followed by incubation at 37\u0026deg;C for 15 minutes and the reactions were terminated by adding 1 mL of 5% ice-cooled trichloroacetic acid. The samples were centrifuged for 5 minutes at 4,000 x g at room temperature. Then, 200 \u0026micro;L of the supernatant was removed and 50 \u0026micro;L of 5 M NaOH was added to adjust the color. The mixture was then incubated for 10 minutes at room temperature. Afterwards, the absorbance was measured at 410 nm. The amount of p-nitrophenol consumed during the glucuronidation reaction was determined from the sample absorbance by using the standard curve for p-nitrophenol. The UGT enzyme activity was calculated based on the p-nitrophenol consumed in the glucuronidation reaction (Eq.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"545\" height=\"70\"\u003e\u003c/p\u003e\u003cp\u003eThe time of incubation was 15 minutes, and the final protein concentration was 0.38 mg/mL. The assay expressed the UGT activity as nmol p-nitrophenol consumed/min/mg protein, then was calculated to get the percentage activity.\u003c/p\u003e \u003cp\u003eEvaluation of the \u003cem\u003eIn vivo\u003c/em\u003e effect of \u003cem\u003eJ. curcas\u003c/em\u003e on the Pharmacokinetics of Dolutegravir\u003c/p\u003e \u003cp\u003ePharmacokinetics study design\u003c/p\u003e \u003cp\u003eEighty male Wistar rats were used for this study. To determine the sample size, an assumption of a coefficient variation (% CV) due to biological variability\u0026thinsp;\u0026lt;\u0026thinsp;20% between each treatment arm and the control group was used. For each group a minimum power of 80% to detect changes in pharmacokinetic (PK) data was assumed with statistical power of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Thus, a minimum of four animals per group (n\u0026thinsp;=\u0026thinsp;4) is required, and sixteen rats for each group to allow adequate blood sampling, giving a total of 80 rats. The rats were housed under a 12 h light/dark cycle with free access to food and potable water for at least seven days to allow them to acclimatize before use.\u003c/p\u003e \u003cp\u003eThe rats were randomly divided into five groups of sixteen rats each i.e. control, AJC pretreatment (AJC PT), EJC pretreatment (EJC PT), AJC coadministration (AJC CA), and EJC coadministration (EJC CA) groups. The control group received distilled water alone for 7 days; AJC PT group received 200 mg/kg of aqueous \u003cem\u003eJ. curcas\u003c/em\u003e extract alone for 7 days, followed by administration of 10 mg/kg DTG on day 7; EJC PT group received 200 mg/kg of ethanol extract of \u003cem\u003eJ. curcas\u003c/em\u003e alone for 7 days, followed by administration of 10 mg/kg DTG on day 7; AJC CA group received 200 mg/kg aqueous extract of \u003cem\u003eJ. curcas\u003c/em\u003e along with 10 mg/kg DTG for 7 days; and EJC CA group received 200 mg/kg ethanol extract of \u003cem\u003eJ. curcas\u003c/em\u003e along with 10 mg/kg DTG for 7 days. After drug administration, each group was further subdivided into two groups of four rats, such that only two blood samples per time interval (0.5, 1, 2, 4, 6, 8, 12, and 24) were collected from individual animal within 24 h from the retro-orbital plexus under injection ketamine anesthesia. Plasma was obtained by centrifugation at 3000 g for 10 minutes and stored at -20\u003csup\u003e\u0026deg;\u003c/sup\u003eC until HPLC analysis.\u003c/p\u003e \u003cp\u003eHPLC Analysis\u003c/p\u003e \u003cp\u003eA stock solution of DTG was prepared in methanol such that the final concentration was 100 mg/L. The stock solutions were stored at 20\u0026deg;C until they were used for analysis. The stock solutions were diluted and spiked in plasma appropriately to make plasma calibration standard ranging 0.05-1mg/L for DTG.\u003c/p\u003e \u003cp\u003ePlasma concentrations of DTG were determined using a previously validated HPLC method (Yarlagadda et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). For plasma preparation, 200 \u0026micro;L cold acetonitrile was added to 500 \u0026micro;L of plasma calibration standard and test sample. The samples were vortexed for 2 minutes, followed by centrifugation at 1500 g for 5 minutes at room temperature. The resulting supernatants were transferred to a prelabeled tube and evaporated to dryness under nitrogen at 40\u003csup\u003e\u0026deg;\u003c/sup\u003eC. The dried residues were dissolved in 200 \u0026micro;L acetonitrile, vortexed thoroughly and then 20 \u0026micro;L was injected for analysis.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003ein vitro\u003c/em\u003e studies data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM of triplicate samples (n-3). One-way analysis of variance (ANOVA) was used to compare the effects of different concentrations of AJC and EJC with the positive control (PC) on UGT enzymes activity. Statistical analysis was performed using GraphPad Prism version 9.5.0 software (San Diego, CA, USA). IC\u003csub\u003e50\u003c/sub\u003e value and non-linear regression analysis were performed using GraphPad Prism 9.5.0. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003ein vivo\u003c/em\u003e data was analyzed based on a non-compartmental pharmacokinetic model using PKanalix 2024 version (Lixoft, France), pharmacokinetics fitting software to calculate the model-independent pharmacokinetic parameters. The parameters determined were area under the plasma concentration-time curve (AUC), apparent clearance (CL/f), apparent volume of distribution (Vd/f), peak concentration (T\u003csub\u003emax\u003c/sub\u003e), maximum concentration (C\u003csub\u003emax\u003c/sub\u003e), and elimination constant (K\u003csub\u003eel\u003c/sub\u003e). The pharmacokinetic parameters were compared between the five groups using a paired two samples t-test and a two-tailed significance level of p\u0026thinsp;\u0026le;\u0026thinsp;0.05 (GraphPad Prism 9.5.0 San Diego, CA, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePotential inhibition of UGT activity was analyzed using aqueous and ethanol extracts of \u003cem\u003eJ. curcas\u003c/em\u003e at 1000 \u0026micro;g/mL; niflumic acid (NFA) 100 \u0026micro;M was used as positive control since this drug is a known inhibitor of UGT1A enzyme activity. The UGT-mediated reaction was performed in rat liver microsomes to evaluate the effect of AJC and EJC on p-nitrophenol glucuronide formation. NFA significantly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) inhibited enzymatic consumption of p-nitrophenol when compared with the control (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), indicating the proper performance of this inhibitor under the established reaction conditions. Furthermore, EJC exhibited the highest inhibitory effect on UGT1A activity when compared to the remaining groups. As shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, AJC and EJC substantially inhibited UGT1A activity. The AJC and EJC showed highest UGT inhibitory activity at 250 \u0026micro;g/mL when compared to NFA (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, the enzyme inhibitory effect of EJC was dose-dependent up to 250 mg/ml, the enzyme inhibitory effect increased as the extract concentration increased (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHPLC-UV analysis was carried out to quantify the amount of DTG in the rat plasma. The maximum plasma concentration of dolutegravir (C\u003csub\u003emax\u003c/sub\u003e) was increased for AJC PT, EJC PT, AJC CA, and EJC CA group (0.0034, 0.0026, 0.0034, and 0.0047 mg/L respectively) compared to the control group (0.0015 mg/L). The C\u003csub\u003emax\u003c/sub\u003e for EJC CA group was highest (0.047 mg/mL) compared to the other groups. The T\u003csub\u003emax\u003c/sub\u003e values for the control, pre-treatment, and co-administration groups were between 0.5\u0026ndash;1 h (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The non compartmental analysis of single dose DTG result showed that area under the plasma concentration-time curve from time zero extrapolated to 24 h (AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24\u003c/sub\u003e) for AJC PT, EJC PT, AJC CA, and EJC CA were 0.04, 0.025, 0.02, and 0.03 mg.h./L respectively, slightly higher than that of control group 0.023 mg.h./L (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\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\u003eComparative effect of \u003cem\u003eJ. curcas\u003c/em\u003e (200 mg/kg) on the pharmacokinetic parameters of single oral dose of dolutegravir.\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=\"char\" char=\".\" 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=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\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\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAJC PT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEJC PT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAJC CA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEJC CA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAUC\u003c/b\u003e\u003csub\u003e\u003cb\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24\u003c/b\u003e\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC\u003c/b\u003e\u003csub\u003e\u003cb\u003emax\u003c/b\u003e\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.0015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0034\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0026\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0034\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0047\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT\u003c/b\u003e\u003csub\u003e\u003cb\u003emax\u003c/b\u003e\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eK\u003c/b\u003e\u003csub\u003e\u003cb\u003eel\u003c/b\u003e\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCL/f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e381.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e89.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e392.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e488.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e488.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eV\u003c/b\u003e\u003csub\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sub\u003e\u003cb\u003e/f\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4161.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4251.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2593.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1142.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1142.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAUMC\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e91.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMRT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM, n\u0026thinsp;=\u0026thinsp;4 and *p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. DTG - dolutegravir (10mg/kg, p.o), AJC PT- aqueous \u003cem\u003eJ. curcas\u003c/em\u003e extract pretreatment group, EJC PT- ethanol \u003cem\u003eJ. curcas\u003c/em\u003e extract pretreatment group, AJC- CA aqueous \u003cem\u003eJ. curcas\u003c/em\u003e extract coadministration group, EJC CA- ethanol \u003cem\u003eJ. curcas\u003c/em\u003e extract coadministration group. AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;24\u003c/sub\u003e- area under the concentration-time curve (mg.h/L), C\u003csub\u003emax\u003c/sub\u003e- maximum plasma concentration (mg/mL), T\u003csub\u003emax\u003c/sub\u003e- time to reach maximum temperature (h); K\u003csub\u003eel\u003c/sub\u003e- elimination constant; CL/f- apparent clearance (L/h); V\u003csub\u003ed/f\u003c/sub\u003e- apparent volume of distribution (L/kg); AUMC- total area under the first moment curve; MRT- mean residence time.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe screening of herbal medicines for possible herb-drug interactions has gained prominence due to the upsurge in the use of herbal medicines along with the orthodox drugs (Pan et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The risk of HDIs among HIV patients is higher due to the multiple drugs used in the management of HIV infection and associated opportunistic infections (Thomford et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Thus, evaluating herbal extracts for possible HDIs is extremely urgent for antiretroviral drugs. Herb-drug interactions in which herbal medicine is a \u0026ldquo;perpetrator\u0026rdquo; could lead to treatment failure or adverse reactions (Olawoye et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). However, some HDIs may be beneficial; for instance, herbal medicines that increase orthodox drug absorption and bioavailability may increase their efficacy (Lam et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The notable mechanisms of HDIs include modulation of CYP450, UGT, and drug transporters (Jeong et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The inhibition of drug metabolism involving cytochrome P450 enzymes is the most studied, however, there are fewer studies on inhibition of UGT as a mechanism of herb-drug interactions (Detampel et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe concentration dependent inhibition of UGT activity by the aqueous and ethanol extracts of \u003cem\u003eJ. curcas\u003c/em\u003e is in tandem with some reported moderate inhibition of UGT by some other medicinal plants. Liu et al. reported 53 natural and synthetic flavonoids that are potent inhibitors of UGT enzyme activity (Liu et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Thus, findings from this study agree with previous studies on the inhibitory effect of medicinal plant extracts on UGT activity. Concurrent consumption of \u003cem\u003eJ. curcas\u003c/em\u003e leaves with drugs that are substrates of UGT enzymes, such as DTG; could increase their plasma concentrations that can lead to adverse effects and HDI.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003ein vivo\u003c/em\u003e experiment was performed based on the principle that the inhibition of major enzymes UGT1A1 responsible for the metabolism of DTG will lead to an increase in the plasma concentration of DTG when orally administered. Adult male rats were used for this study because of their lower hormonal, body weight, organ size, and metabolic rate variability (Kim et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). There are several reports of ethnomedicinal use of \u003cem\u003eJ. curcas\u003c/em\u003e; this plant contains phytochemicals that are responsible for its pharmacological activities as well as toxic compounds such as phorbol esters (Leyva-Padr\u0026oacute;n et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Thus, there is possibility that its consumption with DTG may have clinically relevant herb-drug interactions.\u003c/p\u003e \u003cp\u003eThe T\u003csub\u003emax\u003c/sub\u003e range for this study correlates with the reported T\u003csub\u003emax\u003c/sub\u003e for DTG (Cottrell et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). The C\u003csub\u003emax\u003c/sub\u003e of DTG increased significantly in the \u003cem\u003eJ. curcas\u003c/em\u003e extract-treated group, indicating increased absorption and bioavailability of the drug. The area under the plasma concentrations curve (AUC) of DTG was also increased in all the extract-treated groups. The AUC and C\u003csub\u003emax\u003c/sub\u003e are used to measure the extent of drug bioavailability, which is impacted by the first pass effect (Nduka et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). The AUC, AUMC, Cmax, and MRT that were elevated in the AJC pre-treatment group indicates increased systemic bioavailability of DTG and possible inhibition of UGT which is the enzyme responsible for the metabolism of DTG in the liver. Therefore, concomitant use of \u003cem\u003eJ. curcas\u003c/em\u003e extracts by patient on DTG therapy may be harmful due to the inhibition of UGT enzymes. This observed interaction between DTG and extracts of \u003cem\u003eJ. curcas\u003c/em\u003e leaf may lead to poor adherence, treatment failure, poor patient safety and clinical outcomes. This finding on aqueous extract is important because water extraction is the commonest method of \u003cem\u003eJ. curcas\u003c/em\u003e extract preparation (Dangambo et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Only AUC and C\u003csub\u003emax\u003c/sub\u003e were increased in the ethanolic extracts of \u003cem\u003eJ. curcas\u003c/em\u003e for the pre-treatment and co-administration group indicating possible reduced first past effect.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, \u003cem\u003eJ. curcas\u003c/em\u003e leaf extracts inhibit UGT enzymes activity. This explains the altered DTG pharmacokinetics seen in rats treated with \u003cem\u003eJ. curcas\u003c/em\u003e leaf extracts. The increase in AUC and C\u003csub\u003emax\u003c/sub\u003e of DTG in aqueous and ethanol extracts of \u003cem\u003eJ. curcas\u003c/em\u003e leaf indicates \u003cem\u003ein vivo\u003c/em\u003e inhibition of UGT. Thus, aqueous and ethanol extracts of \u003cem\u003eJ. curcas\u003c/em\u003e leaf could cause herb-drug interactions when co-administered with DTG in Wistar rats. It is therefore recommended that HIV patients on DTG therapy should exercise caution when using extracts of \u003cem\u003eJ. curcas\u003c/em\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eAll authors acknowledge the Tertiary Education Trust Fund (TETFUND) for funding this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e M.O. Ologe: supervised the conducted research, contributed to the research methodology, data analysis, paper writing, revision, and submission; O.A. Yusuf: \u0026nbsp;Conducted research, data analysis, performed the statistical analysis, paper writing, primarily responsible for final content and submission; O. Atolani: co-supervised the conducted research, contributed to the research methodology, data analysis, paper writing, revision, and submission; A.A. Njan: supervision, validation, and participated in paper writing; A.C. Tella: supervision, validation, provided essential reagents and materials and participated in paper writing. The first draft of the manuscript was written by O.A. Yusuf and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e Funding was received for this study from Tertiary Education Trust Fund (TETFUND) for Institution-Based Intervention Grant (IBR) with award number: TETF/DR\u0026amp;D/CE/UNT/AZARE IBR/2023/VOL1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e The datasets analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e, No competing interest declared by the authors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResearch involving human and animal participants This study does not contain any studies on human subjects performed by any of the authors. All animal procedures were performed according to the ethical standards of the University of Ilorin ethical research committee, with approval number UERC/ASN/2021/2292.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAgbenyeku, M. A., Appiah-Opong, R., Obese, E., Biney, R. P., Adakudugu, E. A., Forkuo, A. D., Osei, S. A., Abeka, M. K., \u0026amp; Ameyaw, E. O. (2022). \u003cem\u003eEffect of Xylopic Acid on Cytochrome P450 Enzymes\u003c/em\u003e. https://doi.org/10.1155/2022/4524877\u003c/li\u003e\n\u003cli\u003eBernardo J, V. P. (2024). Herb-drug interactions: A short review on central and peripheral nervous system drugs. \u003cem\u003ePhytother Res.\u003c/em\u003e, \u003cem\u003e38\u003c/em\u003e(4), 1903\u0026ndash;1931.\u003c/li\u003e\n\u003cli\u003eCottrell, M.L., Hadzic, T. \u0026amp; Kashuba, A. D. M. (2013). 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(2023). Exploring the Solubility and Bioavailability of Sodium Salt and Its Free Acid Solid Dispersions of Dolutegravir. \u003cem\u003eAdvances in Pharmacological and Pharmaceutical Sciences\u003c/em\u003e, \u003cem\u003e2023\u003c/em\u003e. https://doi.org/10.1155/2023/7198674\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Tertiary Education Trust Fund (TETFUND)","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":"Herbal interaction, Alternative medicine, Dolutegravir, Jatropha curcas, Human immunodeficiency virus","lastPublishedDoi":"10.21203/rs.3.rs-6232514/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6232514/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose\u003c/b\u003e\u003c/p\u003e \u003cp\u003eConcomitant herbal medicine and antiretroviral therapy can result in adverse effects or diminished drug efficacy. This study determined the effect of \u003cem\u003eJatropha curcas\u003c/em\u003e on UGT1A activity and its implications on dolutegravir (DTG) pharmacokinetics during concomitant administration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe effects of aqueous (AJC) and ethanol (EJC) extracts of \u003cem\u003eJ. curcas\u003c/em\u003e were evaluated in rat liver microsomes, and UGT1A activity was determined using spectrophotometric techniques. Eighty Wistar rats were divided into five groups: control group (water ad libitum, then DTG, 10 mg/kg on day 7), AJC pretreatment (PT) group (AJC 200 mg/kg for 7 days\u0026thinsp;+\u0026thinsp;DTG 10 mg/kg on day 7), EJC PT group (EJC 200 mg/kg for 7 days\u0026thinsp;+\u0026thinsp;DTG 10 mg/kg on day 7), AJC co-administration group (CA) (AJC 200 mg/kg\u0026thinsp;+\u0026thinsp;DTG 10 mg/kg for 7 days), and EJC CA group (EJC 200 mg/kg\u0026thinsp;+\u0026thinsp;DTG 10 mg/kg). On day 8, blood samples were collected at different time intervals and plasma concentration of DTG was determined using high liquid chromatography.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAJC and EJC caused moderate \u003cem\u003ein vitro\u003c/em\u003e inhibition of UGT1A activity with IC\u003csub\u003e50\u003c/sub\u003e 88.02\u0026thinsp;\u0026plusmn;\u0026thinsp;3.41 and 79.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03 respectively. Co-administration of AJC and EJC with dolutegravir demonstrated a significant increase in area under the curve concentration (AUC) and maximum plasma concentration of (C\u003csub\u003emax\u003c/sub\u003e) of dolutegravir.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIt was observed from the result that the co-administration of AJC and EJC with DTG in Wistar rats, triggered herb-drug interactions. Thus, \u003cem\u003eJ. curcas\u003c/em\u003e extracts should be used with caution by HIV patients on DTG therapy.\u003c/p\u003e","manuscriptTitle":"Effect of Modulation of Uridine 5’-Diphospho-Glucuronosyl Transferase 1A Enzymes by Jatropha curcas Extracts on the Pharmacokinetics of Dolutegravir","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-18 08:00:36","doi":"10.21203/rs.3.rs-6232514/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":"febc169d-3f9c-4518-b59a-42654ed04a44","owner":[],"postedDate":"March 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":45824164,"name":"Pharmacokinetics"},{"id":45824165,"name":"Natural Product Chemistry"}],"tags":[],"updatedAt":"2025-03-18T08:00:36+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-18 08:00:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6232514","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6232514","identity":"rs-6232514","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}