Elsevier

Biochemical Pharmacology

Volume 53, Issue 8, 25 April 1997, Pages 1187-1195
Biochemical Pharmacology

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

https://doi.org/10.1016/S0006-2952(97)00100-7Get rights and content

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 Vmax/Km 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 Vmax/Km 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 Ki values of < 1.0 μ.M.

References (22)

  • MF Hebert et al.

    Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic en zyme induction

    Clin Pharmacol Ther

    (1992)
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