Sex-Dependent Differences in Cytochrome P450 3A Activity as Assessed by Midazolam Disposition in Humans: A Meta-Analysis

Abstract

Controversy exists concerning the sex-dependent differences in cytochrome P450 3A activity in humans. Meta-analysis of selected studies may address this question. Meta-analysis was performed on published or unpublished data in terms of sex-dependent differences in midazolam (MDZ) disposition in humans. The following pharmacokinetic parameters were included for the analysis: MDZ oral and systemic clearance, area under the concentration-time curve (AUC) of oral and intravenous MDZ, MDZ oral bioavailability (F), and MDZ gastrointestinal extraction (E(G)). Ten studies including 409 healthy volunteers were identified. Women exhibited 16% higher weight-corrected MDZ oral clearance (P < 0.001) and 20% higher systemic clearance (P = 0.002) than men. No significant difference in the AUC after oral dosing of MDZ was noted between sexes. Women showed lower AUC of intravenous MDZ than men (P = 0.02). No sex-dependent differences were observed in F and E(G). In conclusion, women showed significantly greater hepatic CYP3A activity than men, whereas no sex-dependent difference in intestinal CYP3A activity was observed.