The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)-verapamil in humans

Aims The purpose of this human intestinal perfusion study was to investigat e the effect of ketoconazole on the jejunal permeability and first-pass met abolism of (R)-and (S)-verapamil in humans. Methods A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut(R) perfusion tube in six healthy volunteers. Each perfusion la sted for 200 min and was divided into two periods of 100 min each. The inle t concentration of (R/S)-verapamil was 120 mg 1(-1) in both periods, and ke toconazole was added at 40 mg 1(-1) in period 2. (R/S)-verapamil was also a dministered as a short intravenous infusion of 5 mg, over a period of 10 mi n. The appearance ratios of the CYP3A formed metabolites (R)- and (S)-norve rapamil were also estimated in the outlet jejunal perfusate. Results The effective jejunal permeability (Peff) of both (R)- and (S)-vera pamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P-glycoprotein mediated efflux. How ever, the appearance ratio of both (R)- and (S)-norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of ab sorption into plasma of (R)- and (S)-verapamil increased despite the low do se of ketoconazole added, indicating an inhibition of the gut wall metaboli sm of (R/S)-verapamil by ketoconazole. Conclusions Ketoconazole did not affect the jejunal Peff of (R/S)-verapamil , but: it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of ver apamil. This might be due to ketoconazole being less potent as an inhibitor of P-glycoprotein in than of CYP3A4 in vivo in humans.