Comparative in vitro metabolism of indinavir in primates--a unique stereoselective hydroxylation in monkey.

Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.

Comparative in vitro metabolism of indinavir in primates--a unique stereoselective hydroxylation in monkey.

Xenobiotica. 2000 Feb;30(2):117-29. Unique Identifier : AIDSLINE MED/20181048
Chiba M; Nishime JA; Neway W; Lin Y; Lin JH; Department of Drug Metabolism, Merck Research Laboratories, West; Point, PA 19486, USA. Masato_Chiba@merck.com

Abstract: 1. The in vitro metabolism of indinavir (CRIXIVAN, MK-0639, L-735,524), an HIV protease inhibitor, was evaluated using liver microsomes from cynomolgus monkey, rhesus monkey, chimpanzee and human. Indinavir exhibited marked species differences in metabolism. The overall rate of indinavir metabolism varied > 4-fold among primates (84 pmol/min/mg protein in cynomolgus monkey versus 20.4 pmol/min/mg protein in human) and followed the rank order: cynomolgus monkey > rhesus monkey > chimpanzee > human. 2. The cis-(indan)hydroxylated metabolite of indinavir was formed only in cynomolgus and rhesus monkey livers, whereas trans-(indan)hydroxylation and N-dealkylation were observed as the major metabolites in all primates tested. Inhibition studies with P450-selective inhibitors (ketoconazole, quinine, quinidine) and monoclonal antibodies (against CYP2D6 or CYP3A4) indicated that a cytochrome P450 isoform of the CYP2D subfamily is involved in the formation of the unique cis-(indan) hydroxylated metabolite in monkey, whereas all other oxidative metabolites, including the trans-(indan)hydroxylated metabolite, are formed by CYP3A isoform(s). 3. The present study has demonstrated that monkeys were unique in their abilities to form the stereoselective metabolite and were not appropriate surrogates for the qualitative prediction of indinavir metabolism in human.

Keywords: JOURNAL ARTICLE Animal Antibodies, Monoclonal/PHARMACOLOGY Chromatography, High Pressure Liquid Comparative Study Cytochrome P-450/IMMUNOLOGY/METABOLISM Cytochrome P-450 CYP2D6/IMMUNOLOGY/METABOLISM Debrisoquin/METABOLISM Human Hydroxylases/IMMUNOLOGY/METABOLISM Hydroxylation HIV Protease Inhibitors/*PHARMACOLOGY Indinavir/*METABOLISM Kinetics Microsomes, Liver/METABOLISM Molecular Conformation Molecular Structure Primates Quinidine/PHARMACOLOGY Quinine/PHARMACOLOGY

000630
A0061324

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, Gill Foundation, the National Library of Medicine, Quest Diagnostics, Roche and Trimeris, and donations from users like you. Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2000. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .