Effect of Oral Ketoconazole on Intestinal First-Pass Effect of Midazolam and Fexofenadine in Cynomolgus Monkeys
| Autor: | Toshiyuki Kume, Akihito Ogasawara, Emiko Kazama |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Antifungal Agents CYP3A Midazolam Pharmaceutical Science Pharmacology First pass effect Pharmacokinetics Oral administration Microsomes medicine Animals Humans Drug Interactions Terfenadine ATP Binding Cassette Transporter Subfamily B Member 1 Intestinal Mucosa Fexofenadine CYP3A4 Chemistry Intestines Macaca fascicularis Ketoconazole Liver Cytochrome P-450 CYP3A Inhibitors medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 35:410-418 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | Because the expression of drug-metabolizing enzymes and drug efflux transporters has been shown 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 CYP3A 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 i.v. at doses of 0.3 or 1 mg/kg, respectively, the plasma concentration-time profiles were not influenced by p.o. coadministration of KTZ (20 mg/kg). On the other hand, when MDZ or FEX was administered p.o. at doses of 1 or 5 mg/kg, respectively, concomitant with a dose p.o. 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 toward 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 with those in the respective human samples. These results suggest that monkeys may be an appropriate animal species for evaluating the intestinal first-pass effect of p.o. administered drugs and predicting intestinal DDI related to CYP3A4 and P-gp in humans. |
| Databáze: | OpenAIRE |
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