Does sex influence proximal small intestinal CYP3A or P-GP expression?

Abstract

Background The higher systemic clearance of some CYP3A (whether also P-gp) drug substrates in women vs. men is attributed in part to a higher hepatic CYP3A4 content in women. This, combined with the lack of reported sex differences in the oral clearance of CYP3A substrates suggested a sex-dependent expression of CYP3A in the small intestine but in a pattern opposite to the liver. Methods Duodenal biopsies obtained from healthy men (n=46) and women (n=45) were analyzed by Western blot for CYP3A4, CYP3A5, P-gp, and the control protein villin. Results Among all subjects, CYP3A4 and P-gp content varied 8- and 10-fold, respectively. CYP3A5, which was readily detected in 27% of these predominantly Caucasian individuals, varied 7-fold. For all 3 proteins, a sex difference was not detected (p≥0.55). Comparing the 21 pre-menopausal women (all were aged <45 years) with the 43 men aged <45 years, again no sex differences were detected in CYP3A4 and P-gp content. While a difference in mean log10 (or median) P-gp content was not detected between the pre- and post-menopausal women, mean CYP3A4 content was 20% lower in the post-menopausal individuals (p=0.01). Conclusions The lack of a sex-dependent difference in proximal intestinal CYP3A4 and CYP3A5 could account in part for the lack of reported sex differences in the oral, relative to systemic, clearance of some CYP3A substrates. Ramifications of lower CYP3A4 content in post- vs. pre-menopausal women require further investigation. Clinical Pharmacology & Therapeutics (2005) 77, P2–P2; doi: 10.1016/j.clpt.2004.11.011