The Influence of Sex on Pharmacokinetics

Biologic differences exist between men and women that can result in differences in responses to drugs. Both pharmacokinetic and pharmacodynamic differences between the sexes exist, with more data on pharmacokinetic differences. On average, men are larger than women. Body size differences results in larger distribution volumes and faster total clearance of most medications in men compared to women. Greater body fat in women (until older ages) may increase distribution volumes for lipophilic drugs in women. Total drug absorption does not appear to be significantly affected by sex although absorption rates may be slightly slower in women. Bioavailability after oral drug dosing, for CYP3A substrates in particular, may be somewhat higher in women compared to men. Bioavailability after transdermal drug administration does not appear to be significantly affected by gender; nor does protein binding. Renal processes of glomerular filtration, tubular secretion, and tubular reabsorption appear to be faster in men compared to women whether considered on a mg/kg basis or total body weight basis. Algorithms to estimate glomerular filtration rate incorporate sex as a factor; some also include weight. For hepatic processes, drugs metabolized by Phase I metabolism (oxidation, reduction, and hydrolysis via cytochrome P450’s 1A, 2D6, 2E1), Phase II conjugative metabolism (glucuronidation, conjugation, glucuronyltransferases, methyltransferases, dehydrogenases) and by combined oxidative and conjugation processes are usually cleared faster in men compared to women (mg/kg basis). Metabolism by CYP2C9, CYP2C19, and N-acetyltransferase, appear to be similar in men and women (mg/kg). Clearance of p-glycoprotein substrates appear to be similar in men and women. In contrast, total clearance of a number of CYP3A substrates appear to be mildly or moderately faster (mg/kg) in women compared to men. The clinical significance of reported differences warrants consideration. Clearance reported on a per kg basis directly addresses organ or enzyme clearance. The difference in size between men and women means translating these results to clinical dosage rates should include an adjustment for body size. Unfortunately, this is not standard. Reports of sex differences that persist after considering weight may warrant further dosage adjustments. In addition, investigations are often performed in healthy fasting individuals yet medications are prescribed to patients with confounding influences of disease, co-medications, diet, and social habits. The relative role of sex on pharmacokinetics as compared to genetics, age, disease, social habits and their potential interactions in the clinical setting is not yet fully known but should be routinely considered and further studied.