Behal_2025_Liver.Res_9_253

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.