Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes: Major role of CYP3A

Abstract The metabolism of indinavir, a human immune deficiency virus (HIV) protease inhibitor, has been characterized extensively in rats and humans. All oxidative metabolites found in vivo were formed when indinavir was incubated with NADPH-fortified hepatic and intestinal microsomes obtained from rats and humans. In vitro kinetic studies revealed that V max /K m values (μL/min/mg protein) in rat and human liver microsomes were approximately 8- and 2-fold greater than those in the intestinal microsomes of the corresponding species (55.8 and 6.7 for the liver and intestine, respectively, in rats; 16.5 and 7.7 for the liver and intestine, respectively, in humans). However, when V max /K m was scaled up to intrinsic clearance (mL/min/kg body weight), hepatic intrinsic clearance was much greater than the intestinal clearance by 50- to 200-fold. These results suggest that the liver plays a much greater role in first-pass metabolism of indinavir than the intestine in both species. Consistently, ketoconazole, a selective inhibitor for CYP3A, and an anti-rat CYP3A1 antibody strongly inhibited hepatic and intestinal metabolism of indinavir in both rats and humans, suggesting the involvement of CYP3 A isoforms in both organs. Oral treatment of rats with dexamethasone (50 mg/kg/day for 4 days), a potent CYP3A inducer, increased both hepatic and intestinal metabolism of indinavir by a factor of 7 and 3, respectively. Furthermore, indinavir selectively inhibited 6β-hydroxylase activity of testosterone, a CYP3A marker activity, in rat and human liver microsomes; the interactions between testosterone and indinavir were competitive with K i values of