Received for publication May 8, 2007.
Revised June 7, 2007.
Accepted for publication June 11, 2007.

Role of Small Intestinal Cytochromes P450 in the Bioavailability of Oral Nifedipine

Abstract

To determine the effect of intestinal cytochrome P450 (P450) enzymes on the bioavailability of oral drugs, we have examined the metabolism of nifedipine, an antihypertensive drug and a model substrate of CYP3A4, in mouse models having deficient expression of the NADPH-cytochrome P450 reductase (CPR). Initial studies were performed on Cpr-low (CL) mice, which have substantial decreases in Cpr expression in all tissues examined, including the small intestine. In CL mice, AUC (area under the concentration-time curve) values for blood nifedipine after intraperitoneal and oral dosing were 1.9-fold and 4.0-fold, respectively, higher than in wild-type mice, despite increased expression of multiple P450 enzymes in both liver and intestine. The greater extent of the increase in AUC value for oral than for intraperitoneal nifedipine suggested that intestinal P450s influence the bioavailability of oral nifedipine, a notion supported by results from further studies on LCN and CL-LCN mice. The LCN mice, which have liver-specific Cpr deletion, had 6.9-fold higher AUC values and 2.5-fold higher Cmax values for blood nifedipine than did wild-type mice following oral nifedipine, consistent with the critical role of hepatic P450s in systemic nifedipine clearance. However, in the CL-LCN mice, which have global decreases in Cpr expression in all tissues examined and Cpr deletion in the liver, AUC and Cmax values for oral nifedipine were respectively 2.2-fold and 1.5-fold higher than in LCN mice, confirming that P450-catalyzed metabolism in the small intestine, the portal-of-entry organ for oral drugs, plays an important role in the first-pass clearance of oral nifedipine.

Key words: cytochrome P450, drug disposition, first-pass metabolism, intestinal bioavailability, NADPH cytochrome P450 reductase, pharmacokinetics, transgenic models