ABSTRACT:Cytochromes P450 (P450s) 3A, 2C, and 1A2 constitute the major "pieces" of the human liver P450 "pie" and account, on average, for 40, 25, and 18%, respectively, of total immunoquantified P450s (J Pharmacol Exp Ther 270:414-423, 1994). The P450 profile in the human small intestine has not been fully characterized. Therefore, microsomes prepared from mucosal scrapings from the duodenal/ jejunal portion of 31 human donor small intestines were analyzed by Western blot using selective P450 antibodies. P450s 3A4, 2C9, 2C19, and 2J2 were detected in all individuals and ranged from 8.8 to 150, 2.9 to 27, <0.6 to 3.9, and <0.2 to 3.1 pmol/mg, respectively. CYP2D6 was detected in 29 individuals and ranged from <0.2 to 1.4 pmol/mg. CYP3A5 was detected readily in 11 individuals, with a range (average) of 4.9 to 25 (16) pmol/mg that represented from 3 to 50% of total CYP3A (CYP3A4 ؉ CYP3A5) content. CYP1A1 was detected readily in three individuals, with a range (average) of 3.6 to 7.7 (5.6) pmol/mg. P450s 1A2, 2A6, 2B6, 2C8, and 2E1 were not or only faintly detected. As anticipated, average CYP3A content (50 pmol/mg) was the highest. Excluding CYP1A1, the remaining enzymes had the following rank order: 2C9 > 2C19 > 2J2 > 2D6 (8.4, 1.1, 0.9, and 0.5 pmol/mg, respectively). Analysis of a pooled preparation of the 31 donor specimens substantiated these results. In summary, as in the liver, large interindividual variation exists in the expression levels of individual P450s. On average, CYP3A and CYP2C9 represents the major pieces of the intestinal P450 pie, accounting for 80 and 15%, respectively, of total immunoquantified P450s.

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.

Tacrolimus, a relatively new therapeutic option for patients with corticosteroid-refractory Crohn's disease or ulcerative colitis, is a substrate for the apically directed efflux transporter P-glycoprotein (P-gp). Duodenal biopsy specimens obtained from a patient with corticosteroid-refractory Crohn's disease and with significantly higher-than-average tacrolimus dose requirements were analyzed for P-gp by Western blot. The P-gp content in this patient was more than double that in specimens obtained from 9 of 10 healthy subjects. Elevated intestinal P-gp could have resulted in decreased tacrolimus absorption, thereby leading to decreased blood concentration and decreased efficacy in this patient. The cause and prevalence of this phenomenon are unknown.

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: