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 Meta-analysis was performed on published or unpublished data in terms of sex-dependent differences in midazolam (MDZ) disposition in humans.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 (EG). 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 EG. In conclusion, women showed significantly greater hepatic CYP3A activity than men, whereas no sex-dependent difference in intestinal CYP3A activity was observed.
Footnotes
Z.Y.H. and Y.-S.Z. share co-first authorship.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.031328.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- MDZ
- midazolam
- OM
- AIC, area under the curve
- F
- MDZ oral bioavailability
- EG
- gastrointestinal extraction
- WMD
- weighted mean difference
- SMD
- standardized mean difference
- 95% CI
- 95% confidence intervals
- CLpo
- weight-corrected midazolam oral clearance
- CLiv
- weight-corrected MDZ systemic clearance
- AUCpo
- AUC of oral MDZ
- AUCiv
- area under the concentration-time curve of intravenous MDZ.
- Received November 20, 2009.
- Accepted February 17, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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