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Drug Metabolism and Disposition Fast Forward
First published on December 17, 2004; DOI: 10.1124/dmd.104.002469

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Received for publication September 21, 2004.
Revised December 6, 2004.
Accepted for publication December 16, 2004.

DO MEN AND WOMEN DIFFER IN PROXIMAL SMALL INTESTINAL CYP3A OR P-GLYCOPROTEIN EXPRESSION?

Mary F. Paine 1*, Shana S. Ludington 1, Mei-Ling Chen 2, Paul W. Stewart 1, Shiew-Mei Huang 2, Paul B. Watkins 1

1 University of North Carolina 2 Food and Drug Administration

* Address correspondence to: E-mail: mpaine{at}med.unc.edu

Abstract

The higher systemic clearance of some CYP3A4 (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 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 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 Caucasian individuals, varied 7-fold. For all 3 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 Caucasians (n=74) or to individuals with undetectable CYP3A5. 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. Comparing the pre- with post-menopausal women, mean CYP3A4 content was 20% lower in the post-menopausal 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 CYP3A4 content in post- vs. pre-menopausal women require further investigation.


Key words: CYP expression, CYP3A, extrahepatic cytochrome P450, extrahepatic drug metabolism, gender differences, p-glycoprotein


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