Metabolic Extraction of Nifedipine during Absorption from the Rat Small Intestine

Abstract

  Nifedipine is one of drugs that have been suggested to undergo significant first-pass metabolism by cytochrome P450 (CYP) 3A in the intestine, based mainly on pharmacokinetic analyses of in vivo observations. To further substantiate this suggestion, we examined the metabolic extraction of nifedipine from the rat small intestine, using intestine perfused in situ by a single-pass technique and microsomes in vitro. When the intestinal lumen was perfused with nifedipine solution (30 μM) at the flow rate of 0.15 mL/min and steady-state was achieved, the fraction that disappeared from the intestinal lumen (F_a) and the fraction absorbed into the mesenteric venous blood (F_a,b) was 0.26 and 0.13, respectively. Thus, F_a,b was 50% smaller than F_a, indicating a significant extraction of nifedipine during passage through the intestinal mucosa. When ketoconazole (40 μM), a specific inhibitor of CYP3A, was added to the perfusion solution, F_a,b was increased to a level comparable with F_a, while F_a remained unchanged, suggesting the complete inhibition of metabolic extraction by CYP3A. A similar result was obtained for cyclosporin A (40 μM), another specific CYP3A inhibitor. In intestinal microsomes, the metabolic degradation of nifedipine (1 μM) was almost completely inhibited by ketoconazole (10 μM) and cyclosporin A (10 μM), consistent with the results in the perfused intestine. It was also found in intestinal microsomes that anti-rat CYP3A2 antibody can inhibit nifedipine metabolism completely. Thus, the present study demonstrates that nifedipine undergoes significant extraction during passage through the intestinal mucosa, and provides substantial evidence that CYP3A2 is responsible for that.