Abstract
The higher systemic clearance of some CYP3A4 [whether also P-glycoprotein (P-gp)] drug substrates in women versus men is attributed in part to a higher hepatic CYP3A4 content in women. This, combined with the general paucity of reported sex differences in the apparent oral clearance of CYP3A4 substrates, suggested a sex-dependent expression of CYP3A4 in the intestine, but in a pattern opposite to that in the liver. Accordingly, duodenal biopsies obtained from healthy men (n = 46) and women (n = 45) were analyzed, by Western blot, for relative CYP3A4, as well as for CYP3A5 and P-gp, expression levels. Among all subjects, CYP3A4 and P-gp varied 8- and 10-fold, respectively. CYP3A5, which was readily detected in 27% of these predominantly white individuals, varied 7-fold. For all three proteins, a sex difference was not detected (p ≥ 0.55). The lack of a difference remained for CYP3A4 and P-gp when the analysis was restricted to white individuals (n = 74) or to individuals with undetectable CYP3A5. Comparing the 21 premenopausal women (all were aged <45 years) with the 43 men aged <45 years, again no sex differences were detected in CYP3A4 and P-gp. Comparing the pre- with postmenopausal women, mean CYP3A4 content was 20% lower in the postmenopausal individuals (p = 0.01). The lack of a sex-dependent difference in proximal intestinal CYP3A4 could account, in part, for the lack of reported sex differences in the oral, relative to systemic, clearance of some CYP3A4 substrates. Ramifications of lower intestinal CYP3A4 content in post- versus premenopausal women require further investigation.
Footnotes
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This work was supported by the Office of Women's Health, Food and Drug Administration, and the National Institutes of Health (RR00046 and GM38149). The views presented in this article do not necessarily reflect those of the Food and Drug Administration.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002469.
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ABBREVIATIONS: P-gp, P-glycoprotein; PVDF, polyvinylidene difluoride; PBS-T, phosphate-buffered saline containing 0.3% Tween 20; IOD, integrated optical density; PE, protein equivalent(s); GH, growth hormone.
- Received September 21, 2004.
- Accepted December 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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