Received for publication June 5, 2006.
Revised November 28, 2006.
Accepted for publication November 29, 2006.

Effect of Oral Ketoconazole on Intestinal First-pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys

Abstract

Since the expression of drug metabolizing enzymes and drug efflux transporters has been demonstrated in the intestine, the contribution of this tissue to the first-pass effect has become of significant interest. Consequently, a comprehensive understanding of the absorption barriers in key preclinical species would be useful for the precise characterization of drug candidates. In the present investigation, we evaluated the intestinal first-pass effect of midazolam (MDZ) and fexofenadine (FEX), typical substrates for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), respectively, with ketoconazole (KTZ) as a potent dual CYP3A/P-gp inhibitor, in cynomolgus monkeys. When MDZ or FEX was administered intravenously, at doses of 0.3 mg/kg or 1 mg/kg, respectively, the plasma concentration-time profiles were not influenced by oral coadministration of KTZ (20 mg/kg). On the other hand, when MDZ or FEX was administered orally, at doses of 1 mg/kg or 5 mg/kg, respectively, concomitant with an oral dose of KTZ (20 mg/kg), significant increases were observed in the area under the plasma concentration-time curves of MDZ or FEX (22-fold in MDZ and 3-fold in FEX). These findings indicate that both CYP3A and P-gp play a key role in the intestinal barrier and that inhibition of intestinal CYP3A/P-gp activities contributes exclusively towards the drug-drug interactions (DDI) with KTZ. Additionally, the K_i values of the antifungal agents, KTZ, itraconazole and fluconazole, for MDZ 1'-hydroxylation in monkey intestinal and liver microsomes were comparable to those in the respective human samples. These results suggest that monkeys might be an appropriate animal species for evaluating the intestinal first-pass effect of orally administered drugs and predicting intestinal DDI related to CYP3A4 and P-gp in humans.

Key words: bioavailability, CYP inhibition, CYP3A, drug-drug interactions, first-pass metabolism, intestinal bioavailability, p-glycoprotein