Sex differences in hepatic enzymes and transporters involved in pharmacokinetics

Abstract

Females experience adverse drug reactions at approximately twice the rate of males, contributing to drug-related morbidity and mortality in the United States. This disparity has been strongly associated with sex-based differences in pharmacokinetics. Hepatic drug-metabolizing enzymes and transporters, key regulators of pharmacokinetics, exhibit notable sex-based differences in expression and/or activity. However, findings on the sex-specific impacts of these enzymes and transporters are often scattered, highlighting the need for a comprehensive and up-to-date overview of knowledge in this area. This review compiles and analyzes existing data on sex differences in the expression and activity of clinically relevant hepatic drug-metabolizing enzymes and transporters across species, such as cytochrome P450s, UDP-glucuronosyltransferase, carboxylesterases, P-glycoprotein, breast cancer resistance protein, multidrug resistance-associated protein, organic anion-transporting polypeptides and organic cation transporters. It also summarizes how these differences influence clinical pharmacokinetics, adverse drug reactions, and drug dosing regimens. Furthermore, we explore potential underlying mechanisms, including the influence of sex hormones, sex chromosomes and lifestyle-related factors. Lastly, we discuss clinical implications and future directions in the field, highlighting the urgent need for more human-centered research to clarify the sex-specific impact on drug metabolism and transport in human. Such effort will support the development of sex-informed pharmacotherapy strategies that ultimately reduce adverse drug reactions and improve therapeutic outcomes for patients.

Keywords

Sex differences / Drug-metabolizing enzymes / Transporters / Drug metabolism / Pharmacokinetics (PK) / Adverse drug reaction (ADR)

Authors’ contributions

Mehak Behal: Writing - review & editing, Writing - original draft. Zachary McCalla: Writing - original draft, Writing - review & editing. Xinwen Wang: Writing - review & editing, Writing -original draft, Conceptualization, Supervision.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

[1] Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014; 509:282-283. https://doi.org/10.1038/509282a.

[2] Clayton JA. Studying both sexes: a guiding principle for biomedicine. FASEB J. 2016; 30:519-524. https://doi.org/10.1096/fj.15-279554.

[3] Oi Yan Chan J, Moullet M, Williamson B, Arends RH, Pilla Reddy V. Harnessing clinical trial and real-world data towards an understanding of sex effects on drug pharmacokinetics, pharmacodynamics and efficacy. Front Pharmacol. 2022; 13:874606. https://doi.org/10.3389/fphar.2022.874606.

[4] Doogue MP, Polasek TM. The ABCD of clinical pharmacokinetics. Ther Adv Drug Saf. 2013; 4:5-7. https://doi.org/10.1177/2042098612469335.

[5] Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol. 2009; 76:215-228. https://doi.org/10.1124/mol.109.056705.

[6] Siddiqui MK, Luzum J, Coenen M, Mahmoudpour SH. Editorial: pharmaco-genomics of adverse drug reactions. Front Genet. 2022; 13:859909. https://doi.org/10.3389/fgene.2022.859909.

[7] Zucker I, Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol Sex Differ. 2020; 11:32. https://doi.org/10.1186/s13293-020-00308-5.

[8] VanHouten JP, Rudd RA, Ballesteros MF, Mack KA.Drug overdose deaths among women aged 30-64 years — united States, 1999-2017. MMWR Morb Mortal Wkly Rep. 2019; 68:1-5. https://doi.org/10.15585/mmwr.mm6801a1.

[9] Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011; 2011:187103. https://doi.org/10.1155/2011/187103.

[10] Datz FL, Christian PE, Moore J. Gender-related differences in gastric emptying. J Nucl Med. 1987; 28:1204-1207.

[11] Moyer AM, Matey ET, Miller VM. Individualized medicine: sex, hormones, genetics, and adverse drug reactions. Pharmacol Res Perspect. 2019; 7:e00541. https://doi.org/10.1002/prp2.541.

[12] Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharma-codynamics. Clin Pharmacokinet. 2009; 48:143-157. https://doi.org/10.2165/00003088-200948030-00001.

[13] Ruiz ML, Mottino AD, Catania VA, Vore M. Hormonal regulation of hepatic drug biotransformation and transport systems. Compr Physiol. 2013; 3: 1721-1740. https://doi.org/10.1002/cphy.c130018.

[14] Talevi A, Bellera CL. Phase 0 and Phase III transport. In: Encyclo-pedia The ADME. Cham: Springer; 2021:1-8. https://doi.org/10.1007/978-3-030-51519-5_66-1.

[15] Omiecinski CJ, Vanden Heuvel JP, Perdew GH, Peters JM. Xenobiotic meta-bolism, disposition, and regulation by receptors: from biochemical phe-nomenon to predictors of major toxicities. Toxicol Sci. 2011; 120:S49-S75. https://doi.org/10.1093/toxsci/kfq338.

[16] Iyanagi T. Molecular mechanism of phase I and phase II drug-metabolizing enzymes: implications for detoxification. Int Rev Cytol. 2007; 260:35-112. https://doi.org/10.1016/S0074-7696(06)60002-8.

[17] Zhao M, Ma J, Li M, et al. Cytochrome P450 enzymes and drug metabolism in humans. Int J Mol Sci. 2021; 22:12808. https://doi.org/10.3390/ijms222312808.

[18] Beedham C. The role of non-P450 enzymes in drug oxidation. Pharm World Sci. 1997; 19:255-263. https://doi.org/10.1023/A:1008668913093.

[19] Fukami T, Yokoi T. The emerging role of human esterases. Drug Metab Pharmacokinet. 2012; 27:466-477. https://doi.org/10.2133/dmpk.dmpk-12-rv-042.

[20] Sharma SS, Sharma S, Zhao J, Bureik M. Mutual influence of human cyto-chrome P450 enzymes and UDP-glucuronosyltransferases on their respective activities in recombinant fission yeast. Biomedicines. 2023; 11:281. https://doi.org/10.3390/biomedicines11020281.

[21] Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol. 2013; 45:1121-1132. https://doi.org/10.1016/j.biocel.2013.02.019.

[22] Meech R, Hu DG, McKinnon RA, et al. The UDP-Glycosyltransferase (UGT) superfamily: new members, new functions, and novel paradigms. Physiol Rev. 2019; 99:1153-1222. https://doi.org/10.1152/physrev.00058.2017.

[23] Isvoran A, Peng Y, Ceauranu S, Schmidt L, Nicot AB, Miteva MA. Pharmaco-genetics of human sulfotransferases and impact of amino acid exchange on Phase II drug metabolism. Drug Discov Today. 2022; 27:103349. https://doi.org/10.1016/j.drudis.2022.103349.

[24] Pote˛ ga A. Glutathione-mediated conjugation of anticancer drugs: an over-view of reaction mechanisms and biological significance for drug detoxifi-cation and bioactivation. Molecules. 2022; 27:5252. https://doi.org/10.3390/molecules27165252.

[25] van Vugt-Lussenburg BMA, Capinha L, Reinen J, et al. “Commandeuring” xenobiotic metabolism: advances in understanding xenobiotic metabolism. Chem Res Toxicol. 2022; 35:1184-1201. https://doi.org/10.1021/acs.chemrestox.2c00067.

[26] Annotation of FDA label for isoniazid/pyrazinamide/rifampin and NAT2. PharmGKB.

[27] Sychev DA, Shuev GN, Suleymanov SS, et al. Comparison of CYP2C9, CYP2C19, CYP2D6, ABCB1, and SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations. Pharmgenomics Pers Med. 2017; 10:93-99. https://doi.org/10.2147/PGPM.S129665.

[28] Yang L, Price ET, Chang CW, et al. Gene expression variability in human hepatic drug metabolizing enzymes and transporters. PLoS One. 2013; 8: e60368. https://doi.org/10.1371/journal.pone.0060368.

[29] Wang X, He B, Shi J, Li Q, Zhu HJ. Comparative proteomics analysis of human liver microsomes and S9 fractions. Drug Metab Dispos. 2020; 48:31-40. https://doi.org/10.1124/dmd.119.089235.

[30] Rodríguez-Antona C, Donato MT, Pareja E, Gómez-Lech ón MJ, Castell JV. Cytochrome P-450 mRNA expression in human liver and its relationship with enzyme activity. Arch Biochem Biophys. 2001; 393:308-315. https://doi.org/10.1006/abbi.2001.2499.

[31] Table of Pharmacogenomic Biomarkers in Drug Labeling. FDA. Published online September 23, 2024.

[32] Gaither K, Singh DK, Yue GE, et al. Interplay of alcohol intake, smoking, and sex on the protein abundance of hepatic drug metabolizing enzymes and transporters in humans. J Pharmacol Exp Ther. 2024; 389:237. https://doi.org/10.1124/jpet.237.100511.

[33] Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013; 138:103-141. https://doi.org/10.1016/j.pharmthera.2012.12.007.

[34] Wolbold R, Klein K, Burk O, et al. Sex is a major determinant of CYP3A4 expression in human liver. Hepatology. 2003; 38:978-988. https://doi.org/10.1053/jhep.2003.50393.

[35] Sakuma T, Kawasaki Y, Jarukamjorn K, Nemoto N. Sex differences of drug-metabolizing enzyme: female predominant expression of human and mouse cytochrome P450 3A isoforms. J Health Sci. 2009; 55:325-337. https://doi.org/10.1248/jhs.55.325.

[36] George J, Byth K, Farrell GC. Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver. Biochem Pharmacol. 1995; 50:727-730. https://doi.org/10.1016/0006-2952(95)00192-3.

[37] Fashe MM, Miner TA, Collazo VL, et al. Impact of sex and pregnancy on he-patic CYP3A4 expression and activity in a humanized mouse model. Drug Metab Dispos. 2025; 53:100025. https://doi.org/10.1016/j.dmd.2024.100025.

[38] Evelo A, Leegwater E, Visser LE.Sex differences in pharmacokinetics, phar-macodynamics, and adverse drug reactions of cardiovascular drugs. In: AHEM Maas, E Gerdts, Springer Nature Switzerland;eds. Manual of Cardiovascular Disease in Women. 2024:445-459. https://doi.org/10.1007/978-3-031-65952-2_32.

[39] Kahan BD, Kramer WG, Wideman C, Flechner SM, Lorber MI, Van Buren CT. Demographic factors affecting the pharmacokinetics of cyclosporine esti-mated by radioimmunoassay. Transplantation. 1986; 41:459-464. https://doi.org/10.1097/00007890-198604000-00009.

[40] Austin KL, Mather LE, Philpot CR, McDonald PJ. Intersubject and dose-related variability after intravenous administration of erythromycin. Br J Clin Pharmacol. 1980; 10:273-279. https://doi.org/10.1111/j.1365-2125.1980.tb01755.x.

[41] Krecic-Shepard ME, Park K, Barnas C, Slimko J, Kerwin DR, Schwartz JB. Race and sex influence clearance of nifedipine: results of a population study. Clin Pharmacol Ther. 2000; 68:130-142. https://doi.org/10.1067/mcp.2000.108678.

[42] Inagaki K, Inagaki M, Kataoka T, Sekido I, Gill MA, Nishida M. A wide inter-individual variability of urinary 6beta-hydroxycortisol to free cortisol in 487 healthy Japanese subjects in near basal condition. Ther Drug Monit. 2002; 24: 722-727. https://doi.org/10.1097/00007691-200212000-00007.

[43] Chen M, Ma L, Drusano GL, Bertino JS, Nafziger AN. Sex differences in CYP3A activity using intravenous and oral midazolam. Clin Pharmacol Ther. 2006; 80: 531-538. https://doi.org/10.1016/j.clpt.2006.08.014.

[44] Krecic-Shepard ME, Barnas CR, Slimko J, Schwartz JB. Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific differences after oral administration of verapamil. Clin Pharmacol Ther. 2000; 68: 286-292. https://doi.org/10.1067/mcp.2000.109356.

[45] Lopes GS, Bielinski SJ, Moyer AM, et al. Sex differences in associations be-tween CYP2D6 phenotypes and response to opioid analgesics. Pharmge-nomics Pers Med. 2020; 13:71-79. https://doi.org/10.2147/PGPM.S239222.

[46] Xie HG, Huang SL, Xu ZH, Xiao ZS, He N, Zhou HH. Evidence for the effect of gender on activity of (S)-mephenytoin 4’-hydroxylase (CYP2C19) in a Chinese population. Pharmacogenetics. 1997; 7:115-119. https://doi.org/10.1097/00008571-199704000-00004.

[47] Gerges SH, El-Kadi AOS. Sexual dimorphism in the expression of cytochrome P450 enzymes in rat heart, liver, kidney, lung, brain, and small intestine. Drug Metab Dispos. 2023; 51:81-94. https://doi.org/10.1124/dmd.122.000915.

[48] Yang L, Li Y, Hong H, et al. Sex differences in the expression of drug-metabolizing and transporter genes in human liver. J Drug Metab Toxicol. 2012; 3:1000119. https://doi.org/10.4172/2157-7609.1000119.

[49] Penaloza CG, Estevez B, Han DM, Norouzi M, Lockshin RA, Zakeri Z. Sex-dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA. FASEB J. 2014; 28:966-977. https://doi.org/10.1096/fj.13-233320.

[50] Ou-Yang DS, Huang SL, Wang W, et al. Phenotypic polymorphism and gender-related differences of CYP1A2 activity in a Chinese population. Br J Clin Pharma-col. 2000; 49:145-151. https://doi.org/10.1046/j.1365-2125.2000.00128.x.

[51] California TC PhD in Pharmacology Clinical Lecturer University of California.Riverside school of medicine Riverside. Gender differences in pharmacokinetics. www.uspharmacist.com/article/gender-differences-in-pharmacokinetics. Accessed 27 March 2025.

[52] Scandlyn MJ, Stuart EC, Rosengren RJ. Sex-specific differences in CYP 450 isoforms in humans. Expert Opin Drug Metab Toxicol. 2008; 4:413-424. https://doi.org/10.1517/17425255.4.4.413.

[53] Relling MV, Lin JS, Ayers GD, Evans WE. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther. 1992; 52:643-658. https://doi.org/10.1038/clpt.1992.203.

[54] Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme ac-tivity in human liver microsomes and inducibility in cultured human hepa-tocytes. Toxicol Appl Pharmacol. 2004; 199:193-209. https://doi.org/10.1016/j.taap.2004.01.010.

[55] Skaanild MT, Friis C. Cytochrome P450 sex differences in minipigs and con-ventional pigs. Pharmacol Toxicol. 1999; 85:174-180. https://doi.org/10.1111/j.1600-0773.1999.tb00088.x.

[56] Fu ZD, Csanaky IL, Klaassen CD. Effects of aging on mRNA profiles for drug-metabolizing enzymes and transporters in livers of male and female mice. Drug Metab Dispos. 2012; 40:1216-1225. https://doi.org/10.1124/dmd.111.044461.

[57] Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver mi-crosomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994; 270: 414-423.

[58] Finnström N, Ask B, Dahl ML, Gadd M, Rane A. Intra-individual variation and sex differences in gene expression of cytochromes P450 in circulating leu-kocytes. Pharmacogenomics J. 2002; 2:111-116. https://doi.org/10.1038/sj.tpj.6500086.

[59] Al Koudsi N, Hoffmann EB, Assadzadeh A, Tyndale RF.Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiologic, environmental, and epigenetic factors. Eur J Clin Pharmacol. 2010; 66:239-251. https://doi.org/10.1007/s00228-009-0762-0.

[60] Sinues B, Fanlo A, Mayayo E, et al. CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and oral contraceptives. Hum Exp Toxicol. 2008; 27:367-372. https://doi.org/10.1177/0960327107082224.

[61] Lamba V, Lamba J, Yasuda K, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitu-tive androstane receptor) expression. J Pharmacol Exp Ther. 2003; 307: 906-922. https://doi.org/10.1124/jpet.103.054866.

[62] Hoffman SM, Nelson DR, Keeney DS. Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19. Pharmacogenetics. 2001; 11:687-698. https://doi.org/10.1097/00008571-200111000-00007.

[63] Mang ó K, Kiss áF, Fekete F, Erd }os R, Monostory K. CYP2B6 allelic variants and non-genetic factors influence CYP2B6 enzyme function. Sci Rep. 2022; 12: 2984. https://doi.org/10.1038/s41598-022-07022-9.

[64] Naraharisetti SB, Lin YS, Rieder MJ, et al. Human liver expression of CYP2C8: gender, age, and genotype effects. Drug Metab Dispos. 2010; 38:889-893. https://doi.org/10.1124/dmd.109.031542.

[65] Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998; 45:525-538. https://doi.org/10.1046/j.1365-2125.1998.00721.x.

[66] Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs. 1995; 50:222-239. https://doi.org/10.2165/00003495-199550020-00003.

[67] H€ agg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol. 2001; 51:169-173. https://doi.org/10.1111/j.1365-2125.2001.01328.x.

[68] Park PW, Seo YH, Ahn JY, Kim KA, Park JY. Effects of age and gender on the cytochrome P450 2D6 activity in a Korean population. J Clin Pharm Ther. 2021; 46:1659-1664. https://doi.org/10.1111/jcpt.13507.

[69] Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharm Ther. 1999; 24:339-346. https://doi.org/10.1046/j.1365-2710.1999.00246.x.

[70] Yoon S, Jeong S, Jung E, et al. Effect of CYP3A4 metabolism on sex differences in the pharmacokinetics and pharmacodynamics of zolpidem. Sci Rep. 2021; 11:19150. https://doi.org/10.1038/s41598-021-98689-z.

[71] Westlind-Johnsson A, Malmebo S, Johansson A, et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos. 2003; 31:755-761. https://doi.org/10.1124/dmd.31.6.755.

[72] Thangavel C, Boopathi E, Shapiro BH. Inherent sex-dependent regulation of human hepatic CYP3A5. Br J Pharmacol. 2013; 168:988-1000. https://doi.org/10.1111/j.1476-5381.2012.02222.x.

[73] Anakk S, Ku CY, Vore M, Strobel HW. Insights into gender bias: rat cyto-chrome P450 3A9. J Pharmacol Exp Ther. 2003; 305:703-709. https://doi.org/10.1124/jpet.102.048090.

[74] Schwarz M, Russell DW, Dietschy JM, Turley SD. Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. J Lipid Res. 2001; 42:1594-1603.

[75] Shi J, Wang X, Eyler RF, et al. Association of oseltamivir activation with gender and carboxylesterase 1 genetic polymorphisms. Basic Clin Pharmacol Toxicol. 2016; 119:555-561. https://doi.org/10.1111/bcpt.12625.

[76] Chrostek L, Jelski W, Szmitkowski M, Puchalski Z. Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde de-hydrogenase in humans. J Clin Lab Anal. 2003; 17:93-96. https://doi.org/10.1002/jcla.10076.

[77] Quintanilla ME, Tampier L, Sapag A, Gerdtzen Z, Israel Y.Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective. Am J Physiol Endocrinol Metab. 2007; 293: E531-E537. https://doi.org/10.1152/ajpendo.00187.2007.

[78] Shi J, Wang X, Nguyen JH, et al. Dabigatran etexilate activation is affected by the CES 1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol. 2016; 119:76-84. https://doi.org/10.1016/j.bcp.2016.09.003.

[79] Falls JG, Blake BL, Cao Y, Levi PE, Hodgson E. Gender differences in hepatic expression of flavin-containing monooxygenase isoforms (FMO1, FMO3, and FMO5) in mice. J Biochem Toxicol. 1995; 10:171-177. https://doi.org/10.1002/jbt.2570100308.

[80] Cherrington NJ, Cao Y, Cherrington JW, Rose RL, Hodgson E. Physiological factors affecting protein expression of flavin-containing monooxygenases 1, 3 and 5. Xenobiotica. 1998; 28:673-682. https://doi.org/10.1080/004982598239254.

[81] Ripp SL, Itagaki K, Philpot RM, Elfarra AA. Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes. Drug Metab Dispos. 1999; 27:46-52.

[82] Huang Y, Shan Y, Zhang W, et al. Deciphering genetic causes for sex differ-ences in human health through drug metabolism and transporter genes. Nat Commun. 2023; 14:175. https://doi.org/10.1038/s41467-023-35808-6.

[83] Buckley DB, Klaassen CD.Mechanism of gender-divergent UDP-glucur-onosyltransferase mRNA expression in mouse liver and kidney. Drug Metab Dispos. 2009; 37:834-840. https://doi.org/10.1124/dmd.108.024224.

[84] Muraca M, Fevery J. Influence of sex and sex steroids on bilirubin uridine diphosphate-glucuronosyltransferase activity of rat liver. Gastroenterology. 1984; 87:308-313.

[85] Takeuchi T, Tsutsumi O, Nakamura N, et al. Gender difference in serum bisphenol A levels may be caused by liver UDP-glucuronosyltransferase ac-tivity in rats. Biochem Biophys Res Commun. 2004; 325:549-554. https://doi.org/10.1016/j.bbrc.2004.10.073.

[86] Strasser SI, Smid SA, Mashford ML, Desmond PV. Sex hormones differentially regulate isoforms of UDP-glucuronosyltransferase. Pharm Res. 1997; 14: 1115-1121. https://doi.org/10.1023/A:1012130118186.

[87] Court MH, Hao Q, Krishnaswamy S, et al. UDP-glucuronosyltransferase (UGT) 2B15 pharmacogenetics: UGT2B15 D85Y genotype and gender are major determinants of oxazepam glucuronidation by human liver. J Pharmacol Exp Ther. 2004; 310:656-665. https://doi.org/10.1124/jpet.104.067660.

[88] Gallagher CJ, Balliet RM, Sun D, Chen G, Lazarus P. Sex differences in UDP-glucuronosyltransferase 2B17 expression and activity. Drug Metab Dispos. 2010; 38:2204-2209. https://doi.org/10.1124/dmd.110.035345.

[89] Alnouti Y, Klaassen CD. Mechanisms of gender-specific regulation of mouse sulfotransferases (Sults). Xenobiotica. 2011; 41:187-197. https://doi.org/10.3109/00498254.2010.535923.

[90] Klaassen CD, Liu L, Dunn 2nd RT. Regulation of sulfotransferase mRNA expression in male and female rats of various ages. Chem Biol Interact. 1998; 109:299-313. https://doi.org/10.1016/s0009-2797(97)00141-5.

[91] Barker DF, Walraven JM, Ristagno EH, Doll MA, States JC, Hein DW.Quanti-tative tissue and gene-specific differences and developmental changes in Nat1, Nat2, and Nat3 mRNA expression in the rat. Drug Metab Dispos. 2008; 36:2445-2451. https://doi.org/10.1124/dmd.108.023564.

[92] Court MH. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev. 2010; 42: 209-224. https://doi.org/10.3109/03602530903209288.

[93] Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA. The regulation of steroid action by sulfation and desulfation. Endocr Rev. 2015; 36:526-563. https://doi.org/10.1210/er.2015-1036.

[94] Prysyazhnyuk V, Sydorchuk L, Sydorchuk R, et al. Glutathione-S-transferases genes-promising predictors of hepatic dysfunction. World J Hepatol. 2021; 13: 620-633. https://doi.org/10.4254/wjh.v13.i6.620.

[95] Zhou X, Ma Z, Dong D, Wu B. Arylamine N-acetyltransferases: a structural perspective. Br J Pharmacol. 2013; 169:748-760. https://doi.org/10.1111/bph.12182.

[96] Kaminski WE, Piehler A, Wenzel JJ. ABC A-subfamily transporters: structure, function and disease. Biochim Biophys Acta. 2006; 1762:510-524. https://doi.org/10.1016/j.bbadis.2006.01.011.

[97] Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights. 2013; 7:27-34. https://doi.org/10.4137/DTI.S12519.

[98] Bebawy M, Chetty M. Gender differences in p-glycoprotein expression and function: effects on drug disposition and outcome. Curr Drug Metab. 2009; 10: 322-328. https://doi.org/10.2174/138920009788498996.

[99] Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther. 1995; 275:1011-1018.

[100] Salphati L, Benet LZ. Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Biochem Pharmacol. 1998; 55: 387-395. https://doi.org/10.1016/S0006-2952(97)00436-x.

[101] Rost D, Kopplow K, Gehrke S, et al. Gender-specific expression of liver organic anion transporters in rat. Eur J Clin Invest. 2005; 35:635-643. https://doi.org/10.1111/j.1365-2362.2005.01556.x.

[102] Li N, Hartley DP, Cherrington NJ, Klaassen CD. Tissue expression, ontogeny, and inducibility of rat organic anion transporting polypeptide 4. J Pharmacol Exp Ther. 2002; 301:551-560. https://doi.org/10.1124/jpet.301.2.551.

[103] Hou WY, Xu SF, Zhu QN, Lu YF, Cheng XG, Liu J. Age- and sex-related dif-ferences of organic anion-transporting polypeptide gene expression in livers of rats. Toxicol Appl Pharmacol. 2014; 280:370-377. https://doi.org/10.1016/j.taap.2014.08.020.

[104] Cheng X, Maher J, Lu H, Klaassen CD. Endocrine regulation of gender-divergent mouse organic anion-transporting polypeptide (Oatp) expression. Mol Pharma-col. 2006; 70:1291-1297. https://doi.org/10.1124/mol.106.025122.

[105] Taniguchi T, Zanetti-Yabur A, Wang P, Usyk M, Burk RD, Wolkoff AW. Interindividual diversity in expression of organic anion uptake transporters in normal and cirrhotic human liver. Hepatol Commun. 2020; 4:739-752. https://doi.org/10.1002/hep4.1489.

[106] Courchesne M, Manrique G, Bernier L, et al. Gender differences in pharma-cokinetics: a perspective on contrast agents. ACS Pharmacol Transl Sci. 2023; 7:8-17. https://doi.org/10.1021/acsptsci.3c00116.

[107] Buist SC, Klaassen CD. Rat and mouse differences in gender-predominant expression of organic anion transporter (Oat1-3; Slc22a6-8) mRNA levels. Drug Metab Dispos. 2004; 32:620-625. https://doi.org/10.1124/dmd.32.6.620.

[108] Kobayashi Y, Hirokawa N, Ohshiro N, et al. Differential gene expression of organic anion transporters in male and female rats. Biochem Biophys Res Commun. 2002; 290:482-487. https://doi.org/10.1006/bbrc.2001.6180.

[109] Ciarimboli G. Regulation mechanisms of expression and function of organic cation transporter 1. Front Pharmacol. 2021; 11:607613. https://doi.org/10.3389/fphar.2020.607613.

[110] Kim MH, Shin HJ, Lim SJ, et al. Inter-individual variability in OCT 1 expression and its relationship with OCT1 genotype in liver samples from a Korean population. Drug Metab Pharmacokinet. 2012; 27:530-535. https://doi.org/10.2133/dmpk.dmpk-11-rg-109.

[111] Urakami Y, Nakamura N, Takahashi K, et al. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett. 1999; 461: 339-342. https://doi.org/10.1016/S0014-5793(99)01491-x.

[112] Cheng X, Buckley D, Klaassen CD. Regulation of hepatic bile acid transporters Ntcp and Bsep expression. Biochem Pharmacol. 2007; 74:1665-1676. https://doi.org/10.1016/j.bcp.2007.08.014.

[113] Simon FR, Fortune J, Iwahashi M, Bowman S, Wolkoff A, Sutherland E. Characterization of the mechanisms involved in the gender differences in hepatic taurocholate uptake. Am J Physiol. 1999;276:G556-G565. https://doi.org/10.1152/ajpgi.1999.276.2.G556.

[114] Rohrer PR, Rudraiah S, Goedken MJ, Manautou JE. Is nuclear factor erythroid 2-related factor 2 responsible for sex differences in susceptibility to acetaminophen-induced hepatotoxicity in mice? Drug Metab Dispos. 2014; 42:1663-1674. https://doi.org/10.1124/dmd.114.059006.

[115] Maher JM, Cheng X, Tanaka Y, Scheffer GL, Klaassen CD. Hormonal regulation of renal multidrug resistance-associated proteins 3 and 4 (Mrp3 and Mrp4) in mice. Biochem Pharmacol. 2006; 71:1470-1478. https://doi.org/10.1016/j.bcp.2006.02.005.

[116] Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 2012; 165:1260-1287. https://doi.org/10.1111/j.1476-5381.2011.01724.x.

[117] Kanado Y, Tsurudome Y, Omata Y, et al. Estradiol regulation of P-glycopro-tein expression in mouse kidney and human tubular epithelial cells, impli-cation for renal clearance of drugs. Biochem Biophys Res Commun. 2019; 519: 613-619. https://doi.org/10.1016/j.bbrc.2019.09.021.

[118] Cui YJ, Cheng X, Weaver YM, Klaassen CD. Tissue distribution, gender-divergent expression, ontogeny, and chemical induction of multidrug resis-tance transporter genes (Mdr1a, Mdr1b, Mdr2) in mice. Drug Metab Dispos. 2009; 37:203-210. https://doi.org/10.1124/dmd.108.023721.

[119] Maher JM, Slitt AL, Cherrington NJ, Cheng X, Klaassen CD. Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (Mrp) family in mice. Drug Metab Dispos. 2005; 33:947-955. https://doi.org/10.1124/dmd.105.003780.

[120] Flores K, Manautou JE, Renfro JL. Gender-specific expression of ATP-binding cassette (Abc) transporters and cytoprotective genes in mouse choroid plexus. Toxicology. 2017; 386:84-92. https://doi.org/10.1016/j.tox.2017.05.019.

[121] Simon FR, Fortune J, Iwahashi M, Qadri I, Sutherland E. Multihormonal regulation of hepatic sinusoidal Ntcp gene expression. Am J Physiol Gastrointest Liver Physiol. 2004;287:G782-G794. https://doi.org/10.1152/ajpgi.00379.2003.

[122] Merino G, van Herwaarden AE, Wagenaar E, Jonker JW, Schinkel AH. Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver. Mol Pharmacol. 2005; 67:1765-1771. https://doi.org/10.1124/mol.105.011080.

[123] Sharma S, Mettu VS, Prasad B. Interplay of breast cancer resistance protein (Bcrp/Abcg2), sex, and fed state in oral pharmacokinetic variability of furosemide in rats. Pharmaceutics. 2023; 15:542. https://doi.org/10.3390/pharmaceutics15020542.

[124] Tanaka Y, Slitt AL, Leazer TM, Maher JM, Klaassen CD. Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun. 2005; 326:181-187. https://doi.org/10.1016/j.bbrc.2004.11.012.

[125] Bakker J. The sexual differentiation of the human brain: role of sex hormones versus sex chromosomes. Curr Top Behav Neurosci. 2019; 43:45-67. https://doi.org/10.1007/7854_2018_70.

[126] Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008; 83:1-10. https://doi.org/10.1016/S0074-7742(08)00001-9.

[127] Coig R, Grieve VLB, Cirrincione LR. Clinical pharmacological considerations in transgender medicine. Handb Exp Pharmacol. 2023; 282:41-55. https://doi.org/10.1007/164_2023_665.

[128] Hirano M, Maeda K, Shitara Y, Sugiyama Y. Drug-drug interaction between pitavastatin and various drugs via OATP1B1. Drug Metab Dispos. 2006; 34: 1229-1236. https://doi.org/10.1124/dmd.106.009290.

[129] Lauretta R, Sansone M, Sansone A, Romanelli F, Appetecchia M. Gender in endocrine diseases: role of sex gonadal hormones. Int J Endocrinol. 2018; 2018:4847376. https://doi.org/10.1155/2018/4847376.

[130] Choi SY, Koh KH, Jeong H. Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013; 41: 263-269. https://doi.org/10.1124/dmd.112.046276.

[131] Evangelista EA, Kaspera R, Mokadam NA, Jones 3rd JP, Totah RA. Activity, inhibition, and induction of cytochrome P450 2J2 in adult human primary cardiomyocytes. Drug Metab Dispos. 2013; 41:2087-2094. https://doi.org/10.1124/dmd.113.053389.

[132] Choi SY, Fischer L, Yang K, Chung H, Jeong H. Isoform-specific regulation of cytochrome P450 expression and activity by estradiol in female rats. Biochem Pharmacol. 2011; 81:777-782. https://doi.org/10.1016/j.bcp.2010.12.019.

[133] Ricci MS, Toscano DG, Mattingly CJ, Toscano Jr WA. Estrogen receptor re-duces CYP1A1 induction in cultured human endometrial cells. J Biol Chem. 1999; 274:3430-3438. https://doi.org/10.1074/jbc.274.6.3430.

[134] Kalow W, Tang BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther. 1991; 50:508-519. https://doi.org/10.1038/clpt.1991.176.

[135] Tsuchiya Y, Nakajima M, Yokoi T. Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett. 2005; 227:115-124. https://doi.org/10.1016/j.canlet.2004.10.007.

[136] Higashi E, Fukami T, Itoh M, et al. Human CYP2A6 is induced by estrogen via estrogen receptor. Drug Metab Dispos. 2007; 35:1935-1941. https://doi.org/10.1124/dmd.107.016568.

[137] Koh KH, Jurkovic S, Yang K, et al. Estradiol induces cytochrome P450 2B6 expression at high concentrations: implication in estrogen-mediated gene regulation in pregnancy. Biochem Pharmacol. 2012; 84:93-103. https://doi.org/10.1016/j.bcp.2012.03.016.

[138] Nemoto N, Sakurai J. Glucocorticoid and sex hormones as activating or modulating factors for expression of Cyp2b-9 and Cyp2b-10 in the mouse liver and hepatocytes. Arch Biochem Biophys. 1995; 319:286-292. https://doi.org/10.1006/abbi.1995.1294.

[139] Bandiera S, Dworschak C. Effects of testosterone and estrogen on hepatic levels of cytochromes P450 2C7 and P450 2C11 in the rat. Arch Biochem Biophys. 1992; 296:286-295. https://doi.org/10.1016/0003-9861(92)90574-g.

[140] Sandberg M, Johansson I, Christensen M, Rane A, Eliasson E. The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype. Drug Metab Dispos. 2004; 32:484-489. https://doi.org/10.1124/dmd.32.5.484.

[141] Chen J, Robertson G, Field J, Liddle C, Farrell GC. Effects of bile duct ligation on hepatic expression of female-specific CYP2C12 in male and female rats. Hepatology. 1998; 28:624-630. https://doi.org/10.1002/hep.510280304.

[142] Laine K, Tybring G, Bertilsson L. No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects. Clin Pharmacol Ther. 2000; 68:151-159. https://doi.org/10.1067/mcp.2000.108949.

[143] Li J, Xie M, Wang X, et al. Sex hormones regulate cerebral drug metabolism via brain miRNAs: down-regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol. Br J Pharmacol. 2015; 172:4639-4654. https://doi.org/10.1111/bph.13206.

[144] Konstandi M, Cheng J, Gonzalez FJ. Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver. Am J Physiol Endocrinol Metab. 2013;304:E1118-E1128. https://doi.org/10.1152/ajpendo.00585.2012.

[145] Zu Y, Yang J, Zhang C, Liu D. The pathological mechanisms of estrogen-induced cholestasis: current perspectives. Front Pharmacol. 2021; 12: 761255. https://doi.org/10.3389/fphar.2021.761255.

[146] Belle DJ, Callaghan JT, Gorski JC, et al.The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. Br J Clin Pharmacol. 2002; 53: 67-74. https://doi.org/10.1046/j.0306-5251.2001.01521.x.

[147] Wang H, Strobel HW. Regulation of CYP3A9 gene expression by estrogen and catalytic studies using cytochrome P450 3A9 expressed in Escherichia coli. Arch Biochem Biophys. 1997; 344:365-372. https://doi.org/10.1006/abbi.1997.0230.

[148] Teschke R, Wannagat FJ, Löwendorf F, Strohmeyer G. Hepatic alcohol metabolizing enzymes after prolonged administration of sex hormones and alcohol in female rats. Biochem Pharmacol. 1986; 35:521-527. https://doi.org/10.1016/0006-2952(86)90229-7.

[149] Teschke R, Heymann K. Effect of sex hormones on the activities of hepatic alcohol-metabolizing enzymes in male rats. Enzyme. 1982; 28:268-277. https://doi.org/10.1159/000459111.

[150] Wu L, Hafiz MZ, Guan Y, et al. 17β-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes. Eur J Pharmacol. 2018; 819:98-107. https://doi.org/10.1016/j.ejphar.2017.11.036.

[151] Falls JG, Ryu DY, Cao Y, Levi PE, Hodgson E. Regulation of mouse liver flavin-containing monooxygenases 1 and 3 by sex steroids. Arch Biochem Biophys. 1997; 342:212-223. https://doi.org/10.1006/abbi.1997.9965.

[152] Stern ST, Tallman MN, Miles KK, Ritter JK, Smith PC. Androgen regulation of renal uridine diphosphoglucuronosyltransferase 1A1 in rats. Drug Metab Dispos. 2008; 36:1737-1739. https://doi.org/10.1124/dmd.108.020610.

[153] Jeong H, Choi S, Song JW, Chen H, Fischer JH. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica. 2008; 38:62-75. https://doi.org/10.1080/00498250701744633.

[154] Li YQ, Prentice DA, Howard ML, Mashford ML, Desmond PV. The effect of hormones on the expression of five isoforms of UDP-glucuronosyltransferase in primary cultures of rat hepatocytes. Pharm Res. 1999; 16:191-197. https://doi.org/10.1023/a:1018812021549.

[155] Geier A, Dietrich CG, Gerloff T, et al. Regulation of basolateral organic anion transporters in ethinylestradiol-induced cholestasis in the rat. Biochim Biophys Acta. 2003; 1609:87-94. https://doi.org/10.1016/s0005-2736(02)00657-0.

[156] Suzuki T, Zhao YL, Nadai M, et al. Gender-related differences in expression and function of hepatic P-glycoprotein and multidrug resistance-associated protein (Mrp2) in rats. Life Sci. 2006; 79:455-461. https://doi.org/10.1016/j.lfs.2006.01.024.

[157] Ruiz ML, Villanueva SS, Luquita MG, Vore M, Mottino AD, Catania VA. Ethynylestradiol increases expression and activity of rat liver MRP3. Drug Metab Dispos. 2006; 34:1030-1034. https://doi.org/10.1124/dmd.106.009316.

[158] Ruiz ML, Rigalli JP, Arias A, et al. Induction of hepatic multidrug resistance-associated protein 3 by ethynylestradiol is independent of cholestasis and mediated by estrogen receptor. Drug Metab Dispos. 2013; 41:275-280. https://doi.org/10.1124/dmd.112.047357.

[159] Simon FR, Iwahashi M, Hu LJ, et al. Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion. Am J Physiol Gastrointest Liver Physiol. 2006; 290: G595-G608. https://doi.org/10.1152/ajpgi.00240.2005.

[160] Trauner M, Arrese M, Soroka CJ, et al. The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology. 1997; 113:255-264. https://doi.org/10.1016/s0016-5085(97)70103-3.

[161] Kamisako T, Ogawa H. Alteration of the expression of adenosine triphosphate-binding cassette transporters associated with bile acid and cholesterol transport in the rat liver and intestine during cholestasis. J Gastroenterol Hepatol. 2005; 20: 1429-1434. https://doi.org/10.1111/j.1440-1746.2005.03950.x.

[162] Wielinga PR, van der Heijden I, Reid G, Beijnen JH, Wijnholds J, Borst P. Characterization of the MRP4- and MRP5-mediated transport of cyclic nu-cleotides from intact cells. J Biol Chem. 2003; 278:17664-17671. https://doi.org/10.1074/jbc.M212723200.

[163] Waxman DJ, O’Connor C. Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol. 2006; 20:2613-2629. https://doi.org/10.1210/me.2006-0007.

[164] Jessup SK, Dimaraki EV, Symons KV, Barkan AL. Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men. J Clin Endocrinol Metab. 2003; 88:4776-4780. https://doi.org/10.1210/jc.2003-030246.

[165] Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Womens Health. 2011; 3:25-35. https://doi.org/10.2147/IJWH.S11304.

[166] Gutiérrez-Hurtado IA, et al.Sánchez-Méndez AD, Becerra-Loaiza DS, Loss of the Y chromosome: a review of molecular mechanisms, age inference, and implications for men’s health. Int J Mol Sci. 2024; 25:4230. https://doi.org/10.3390/ijms25084230.

[167] Wang K, Liu H, Hu Q, et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct Target Ther. 2022; 7:374. https://doi.org/10.1038/s41392-022-01211-8.

[168] Mezzalira S, Toffoli G. The effects of sex on pharmacogenetically guided drug treatment. Pharmacogenomics. 2021; 22:959-962. https://doi.org/10.2217/pgs-2021-0088.

[169] Morgan E. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009; 85:434-438. https://doi.org/10.1038/clpt.2008.302.

[170] Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol. 2006; 46:123-149. https://doi.org/10.1146/annurev.pharmtox.46.120604.141059.

[171] Cui Y, Zhu Q, Lou C, et al. Gender differences in cigarette smoking and alcohol drinking among adolescents and young adults in Hanoi, Shanghai, and Taipei. J Int Med Res. 2018; 46:5257-5268. https://doi.org/10.1177/0300060518807292.

[172] Jourová L, Vavreckova M, Zemanova N, et al. Gut microbiome alters the ac-tivity of liver cytochromes P450 in mice with sex-dependent differences. Front Pharmacol. 2020; 11:01303. https://doi.org/10.3389/fphar.2020.01303.

[173] Zucker I, Prendergast BJ. Sex differences in pharmacokinetics. Handb Exp Pharmacol. 2023; 282:25-39. https://doi.org/10.1007/164_2023_669.

[174] Lee SM, Jang JH, Jeong SH. Exploring gender differences in pharmacokinetics of central nervous system related medicines based on a systematic review approach. Naunyn Schmiedebergs Arch Pharmacol. 2024; 397:8311-8347. https://doi.org/10.1007/s00210-024-03190-9.

[175] Roberts RK, Desmond PV, Wilkinson GR, Schenker S. Disposition of chlordi-azepoxide: sex differences and effects of oral contraceptives. Clin Pharmacol Ther. 1979; 25:826-831. https://doi.org/10.1002/cpt1979256826.

[176] Holazo AA, Winkler MB, Patel IH. Effects of age, gender and oral contra-ceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol. 1988; 28:1040-1045. https://doi.org/10.1002/j.1552-4604.1988.tb03127.x.

[177] Divoll M, Greenblatt DJ, Harmatz JS, Shader RI. Effect of age and gender on disposition of temazepam. J Pharm Sci. 1981; 70:1104-1107. https://doi.org/10.1002/jps.2600701004.

[178] Greenblatt DJ, Harmatz JS, von Moltke LL, et al. Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences. J Pharmacol Exp Ther. 2000; 293:435-443.

[179] Kelly DL, Conley RR, Tamminga CA. Differential olanzapine plasma concen-trations by sex in a fixed-dose study. Schizophr Res. 1999; 40:101-104. https://doi.org/10.1016/s0920-9964(99)00053-5.

[180] Kokras N, Dalla C, Papadopoulou-Daifoti Z. Sex differences in pharmacoki-netics of antidepressants. Expert Opin Drug Metab Toxicol. 2011; 7:213-226. https://doi.org/10.1517/17425255.2011.544250.

[181] Ferguson JM, Hill H. Pharmacokinetics of fluoxetine in elderly men and women. Gerontology. 2006; 52:45-50. https://doi.org/10.1159/000089825.

[182] Gex-Fabry M, Eap CB, Oneda B, et al. CYP2D6 and ABCB1 genetic variability: influence on paroxetine plasma level and therapeutic response. Ther Drug Monit. 2008; 30:474-482. https://doi.org/10.1097/FTD.0b013e31817d6f5d.

[183] Stewart JJ, Berkel HJ, Parish RC, et al. Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender. J Clin Pharmacol. 2001; 41:770-778. https://doi.org/10.1177/00912700122010564.

[184] Richens A, Banfield CR, Salfi M, et al. Single and multiple dose pharmacoki-netics of felbamate in the elderly. Br J Clin Pharmacol. 1997; 44:129-134. https://doi.org/10.1046/j.1365-2125.1997.00642.x.

[185] Ibarra M, Vázquez M, Fagiolino P, Derendorf H. Sex related differences on valproic acid pharmacokinetics after oral single dose. J Pharmacokinet Phar-macodyn. 2013; 40:479-486. https://doi.org/10.1007/s10928-013-9323-3.

[186] Martinelli P, Contin M, Scaglione C, Riva R, Albani F, Baruzzi A. Levodopa pharmacokinetics and dyskinesias: are there sex-related differences? Neurol Sci. 2003; 24:192-193. https://doi.org/10.1007/s10072-003-0125-z.

[187] Moody DE, Fang WB, Morrison J, McCance-Katz E. Gender differences in phar-macokinetics of maintenance dosed buprenorphine. Drug Alcohol Depend. 2011; 118:479-483. https://doi.org/10.1016/j.drugalcdep.2011.03.024.

[188] Delahousse J, Wagner AD, Borchmann S, et al. Sex differences in the phar-macokinetics of anticancer drugs: a systematic review. ESMO Open. 2024; 9: 104002. https://doi.org/10.1016/j.esmoop.2024.104002.

[189] Port RE, Daniel B, Ding RW, Herrmann R. Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance. Oncology. 1991; 48: 277-281. https://doi.org/10.1159/000226942.

[190] Mueller F, Büchel B, Köberle D, et al. Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal ma-lignancies: results from a prospective population pharmacokinetic study. Cancer Chemother Pharmacol. 2013; 71:361-370. https://doi.org/10.1007/s00280-012-2018-4.

[191] Chatelut E, Canal P, Brunner V, et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst. 1995; 87:573-580. https://doi.org/10.1093/jnci/87.8.573.

[192] Liu Z, Martin J, Orme L, et al. Gender differences in doxorubicin pharma-cology for subjects with chemosensitive cancers of young adulthood. Cancer Chemother Pharmacol. 2018; 82:887-898. https://doi.org/10.1007/s00280-018-3683-8.

[193] La-Beck NM, Zamboni BA, Gabizon A, et al. Factors affecting the pharmaco-kinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012; 69:43-50. https://doi.org/10.1007/s00280-011-1664-2.

[194] Wade JR, Kelman AW, Kerr DJ, Robert J, Whiting B. Variability in the phar-macokinetics of epirubicin: a population analysis. Cancer Chemother Phar-macol. 1992; 29:391-395. https://doi.org/10.1007/BF00686009.

[195] Joerger M, Huitema AD, van den Bongard DH, Schellens JH, Beijnen JH. Quantitative effect of gender, age, liver function, and body size on the pop-ulation pharmacokinetics of Paclitaxel in patients with solid tumors. Clin Cancer Res. 2006; 12:2150-2157. https://doi.org/10.1158/1078-0432.CCR-05-2069.

[196] Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid pop-ulation pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 2004; 10:3728-3736. https://doi.org/10.1158/1078-0432.CCR-03-0807.

[197] Jen JF, Cutler DL, Pai SM, et al. Population pharmacokinetics of temozolomide in cancer patients. Pharm Res. 2000; 17:1284-1289. https://doi.org/10.1023/a:1026403805756.

[198] Loos WJ, Gelderblom HJ, Verweij J, Brouwer E, de Jonge MJ, Sparreboom A. Gender-dependent pharmacokinetics of topotecan in adult patients. Anticancer Drugs. 2000; 11:673-680. https://doi.org/10.1097/00001813-200010000-00001.

[199] Gallo JM, Laub PB, Rowinsky EK, Grochow LB, Baker SD. Population phar-macokinetic model for topotecan derived from phase I clinical trials. J Clin Oncol. 2000; 18:2459-2467. https://doi.org/10.1200/JCO.2000.18.12.2459.

[200] Tortorici MA, Cohen EE, Pithavala YK, et al. Pharmacokinetics of single-agent axitinib across multiple solid tumor types. Cancer Chemother Pharmacol. 2014; 74:1279-1289. https://doi.org/10.1007/s00280-014-2606-6.

[201] Miles D, Jumbe NL, Lacy S, Nguyen L. Population pharmacokinetic model of cabozantinib in patients with medullary thyroid carcinoma and its application to an exposure-response analysis. Clin Pharmacokinet. 2016; 55: 93-105. https://doi.org/10.1007/s40262-015-0295-x.

[202] Widmer N, Decosterd LA, Csajka C, et al. Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol. 2006; 62:97-112. https://doi.org/10.1111/j.1365-2125.2006.02719.x.

[203] Wu X, Li J, Zhou Y, et al. Relative factors analysis of imatinib trough con-centration in Chinese patients with gastrointestinal stromal tumor. Chemo-therapy. 2018; 63:301-307. https://doi.org/10.1159/000493195.

[204] Judson I, Ma P, Peng B, et al. Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacoki-netic study over time. EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol. 2005; 55:379-386. https://doi.org/10.1007/s00280-004-0876-0.

[205] Keunecke A, Hoefman S, Drenth HJ, Zisowsky J, Cleton A, Ploeger BA. Popu-lation pharmacokinetics of regorafenib in solid tumours: exposure in clinical practice considering enterohepatic circulation and food intake. Br J Clin Pharmacol. 2020; 86:2362-2376. https://doi.org/10.1111/bcp.14334.

[206] Khosravan R, Motzer RJ, Fumagalli E, Rini BI. Population pharmacokinetic/phar-macodynamic modeling of sunitinib by dosing schedule in patients with advanced renal cell carcinoma or gastrointestinal stromal tumor. Clin Pharmacokinet. 2016; 55:1251-1269. https://doi.org/10.1007/s40262-016-0404-5.

[207] Marchand M, Zhang R, Chan P, et al. Time-dependent population PK models of single-agent atezolizumab in patients with cancer. Cancer Chemother Pharmacol. 2021; 88:211-221. https://doi.org/10.1007/s00280-021-04276-4.

[208] Ma P, Yang BB, Wang YM, et al. Population pharmacokinetic analysis of panitumumab in patients with advanced solid tumors. J Clin Pharmacol. 2009; 49:1142-1156. https://doi.org/10.1177/0091270009344989.

[209] Farkouh A, Riedl T, Gottardi R, Czejka M, Kautzky-Willer A. Sex-related dif-ferences in pharmacokinetics and pharmacodynamics of frequently pre-scribed drugs: a review of the literature. Adv Ther. 2020; 37:644-655. https://doi.org/10.1007/s12325-019-01201-3.

[210] Trnavský K. Sex differences in the pharmacokinetics of salicylates. Eur J Clin Pharmacol. 1983; 25:679-682. https://doi.org/10.1007/BF00542358.

[211] Kendall MJ, Quarterman CP, Jack DB, Beeley L. Metoprolol pharmacokinetics and the oral contraceptive pill. Br J Clin Pharmacol. 1982; 14:120-122.

[212] Xie HG, Chen X. Sex differences in pharmacokinetics of oral propranolol in healthy Chinese volunteers. Zhongguo Yaoli Xuebao. 1995; 16:468-470.

[213] Walle T, Walle UK, Cowart TD, Conradi EC. Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects. Clin Pharmacol Ther. 1989; 46:257-263. https://doi.org/10.1038/clpt.1989.136.

[214] Overholser BR, Kays MB, Forrest A, Sowinski KM. Sex-related differences in the pharmacokinetics of oral ciprofloxacin. J Clin Pharmacol. 2004; 44: 1012-1022. https://doi.org/10.1177/0091270004266843.

[215] Sowinski KM, Abel SR, Clark WR, Mueller BA. Effect of gender on the phar-macokinetics of ofloxacin. Pharmacotherapy. 1999; 19:442-446. https://doi.org/10.1592/phco.19.6.442.31044.

[216] Krecic-Shepard ME, Barnas CR, Slimko J, Jones MP, Schwartz JB. Gender-specific effects on verapamil pharmacokinetics and pharmacodynamics in humans. J Clin Pharmacol. 2000; 40:219-230. https://doi.org/10.1177/00912700022008883.

[217] Lopes GS, Bielinski S, Moyer AM, et al. Sex differences in type and occurrence of adverse reactions to opioid analgesics: a retrospective cohort study. BMJ Open. 2021; 11:e044157. https://doi.org/10.1136/bmjopen-2020-044157.

[218] Macaluso M, Zackula R, D’Empaire I, Baker B, Liow K, Preskorn SH. Twenty percent of a representative sample of patients taking bupropion have abnormal, asymp-tomatic electroencephalographic findings. J Clin Psychopharmacol. 2010; 30: 312-317. https://doi.org/10.1097/JCP.0b013e3181dbe1b4.

[219] Manza P, Shokri-Kojori E, Wiers CE, et al. Sex differences in methylphenidate-induced dopamine increases in ventral striatum. Mol Psy-chiatry. 2022; 27:939-946. https://doi.org/10.1038/s41380-021-01294-9.

[220] Yonkers KA, Kando JC, Cole JO, Blumenthal S.Gender differences in phar-macokinetics and pharmacodynamics of psychotropic medication. Am J Psychiatry. 1992; 149:587-595. https://doi.org/10.1176/ajp.149.5.587.

[221] Cubała WJ, Landowski J, Wichowicz HM. Zolpidem abuse, dependence and with-drawal syndrome: sex as susceptibility factor for adverse effects. Br J Clin Phar-macol. 2008; 65:444-445. https://doi.org/10.1111/j.1365-2125.2007.03028.x.

[222] McGregor AJ. The effects of sex and gender on pharmacologic toxicity: im-plications for clinical therapy. Clin Ther. 2017; 39:8-9. https://doi.org/10.1016/j.clinthera.2016.12.007.

[223] Overdyk F, Dahan A, Roozekrans M, van der Schrier R, Aarts L, Niesters M. Opioid-induced respiratory depression in the acute care setting: a compendium of case reports. Pain Manag. 2014; 4:317-325. https://doi.org/10.2217/pmt.14.19.

[224] Samuelson Bannow B. Management of heavy menstrual bleeding on anti-coagulation. Hematology Am Soc Hematol Educ Program. 2020; 2020:533-537. https://doi.org/10.1182/hematology.2020000138.

[225] Shoeb M, Fang MC. Assessing bleeding risk in patients taking anticoagulants. J Thromb Thrombolysis. 2013; 35:312-319. https://doi.org/10.1007/s11239-013-0899-7.

[226] Flory JH, Ky B, Haynes K, et al. Observational cohort study of the safety of digoxin use in women with heart failure. BMJ Open. 2012; 2:e000888. https://doi.org/10.1136/bmjopen-2012-000888.

[227] Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002; 347:1403-1411. https://doi.org/10.1056/NEJMoa021266.

[228] T € aubel J, Prasad K, Rosano G, et al. Effects of the fluoroquinolones moxi-floxacin and levofloxacin on the QT subintervals: sex differences in ventricular repolarization. J Clin Pharmacol. 2020; 60:400-408. https://doi.org/10.1002/jcph.1534.

[229] Rusu A, Munteanu AC, Arbănas¸ i EM, Uivarosi V. Overview of side-effects of antibacterial fluoroquinolones: new drugs versus old drugs, a step forward in the safety profile? Pharmaceutics. 2023; 15:804. https://doi.org/10.3390/pharmaceutics15030804.

[230] Schultheiss JPD, Brand EC, Lamers E, et al. Earlier discontinuation of TNF-α inhibitor therapy in female patients with inflammatory bowel disease is related to a greater risk of side effects. Aliment Pharmacol Ther. 2019; 50: 386-396. https://doi.org/10.1111/apt.15380.

[231] Evaluation of Sex Differences in Clinical Investigations. 2025. May 2, 2025

[232] Questions and Answers: Risk of next-morning Impairment After Use of Insomnia Drugs; FDA Requires Lower Recommended Doses for Certain Drugs Containing Zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). FDA. Published online January 30, 2025.

[233] Greenblatt DJ, Harmatz JS, Roth T. Zolpidem and gender: are women really at risk? J Clin Psychopharmacol. 2019; 39:189-199. https://doi.org/10.1097/JCP.0000000000001026.

[234] Zhao H, DiMarco M, Ichikawa K, et al. Making a ‘sex-difference fact’: ambien dosing at the interface of policy, regulation, women’s health, and biology. Soc Stud Sci. 2023; 53:475-494. https://doi.org/10.1177/03063127231168371.

[235] Xue FS, Tong SY, Liao X, Liu JH, An G, Luo LK. Dose-response and time course of effect of rocuronium in male and female anesthetized patients. Anesth Analg. 1997; 85:667-671. https://doi.org/10.1097/00000539-199709000-00033.