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

Abstract

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 Meta-analysis was performed on published or unpublished data in terms of sex-dependent differences in midazolam (MDZ) disposition in humans.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.The enzyme subfamily cytochrome P450 3A and its two major members-CYP3A4 and, to a lesser extent, CYP3A5-are considered the most important drug-metabolizing enzymes by virtue of their high concentration, strategic localization, and wide substrate specificity (Thummel and Wilkinson, 1998).Midazolam (MDZ) is a selective substrate of CYP3A4 and CYP3A5 and is almost exclusively metabolized by CYP3A to form the primary metabolite 1-hydroxymidazolam. Systemic or apparent oral clearance of MDZ is the most widely tested and accepted biomarker for hepatic and intestinal CYP3A activity (Streetman et al., 2000). Intravenous administration of MDZ reflects only hepatic CYP3A activity, whereas orally administered MDZ is a measure of intestinal and hepatic CYP3A activities (Thummel et al., 1996;Gorski et al., 1998;Streetman et al., 2000).Numerous studies have examined potential sex differences in the metabolic activity of CYP3A. These studies include prospective clinical studies and retrospective analysis of data from previous studies. The findings from clinical studies have been inconsistent or inconclusive. For example, mean MDZ clearances were greater in women in several investigations, reaching statistical significance in some (Greenblatt et al., 1984;Gorski et al., 1998Gorski et al., , 1999Zhu et al., 2003;Chen et al., 2006c;Chung et al., 2006;Kharasch et al., 2007;Hu et al., 2009), whereas other studies found equivalence (Kashuba et al., 1998;Dresser et al., 2003;Floyd et al., 2003;Gorski et al., 2003;Eap et al., 2004;Chen et al., 2006a) or even insignificantly higher clearances in men (Thummel et al., 1996). Results of the largest-scale investigation (41 women and 58 men) showed that systemic clearances were 30% greater in women, but there was no sex difference for oral MDZ (Kharasch et al., 2007).There were two retrospective studies on this topic, and both studies showed significant sex-dependent difference...

Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single‐Time‐Point Oral Midazolam Microdose Phenotype in Healthy Subjects

“…This result differs from that of another study demonstrating higher plasma 4βHC levels in females . Similarly, in multivariable regression analyses, we did not observe any association between sex and MDZ oral clearance or 6βHCL MR despite previous studies showing slightly increased MDZ clearance and urinary 6βHCL MR in women compared to men. While our ability to observe a sex difference in MDZ oral clearance may be attributed to the single‐time‐point microdose strategy, it is likely that our small sample size was a limiting factor.…”

mRNA expression of drug metabolism enzymes and transporter genes at birth using human umbilical cord blood

“…Our finding that CYP3A4 mRNA expression levels at birth were higher in females than males, without taking into account zygosity, is consistent with similar results previously found in adult livers . A gender difference was also reported in the in vivo clearance of CYP3A4 substrates such as nifedipine or midazolam , that is greater in females. None of the other tested genes showed gender differences in expression.…”

Pharmacokinetics of Intravenous Isavuconazole in Solid-Organ Transplant Recipients

“…Female sex, a BMI of Ն18.5 kg/m 2 , and HD are biologically plausible risk factors for reduced AUC 0 -24 h and C trough . Sixty-six percent of ISA is metabolized by hepatic CYP3A (8,9), and women have greater hepatic CYP3A activity than men (18). Cachectic patients (BMI of Ͻ18.5 kg/m 2 ) have decreased plasma and liver volumes and reduced levels of CYP3A4 and other cytochromes, resulting in attenuated ISA metabolism (19).…”