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Title: Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid

Abstract

Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of (/sup 3/H)RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the (/sup 3/H)RA injection, the radioactivity extracted from the liver consisted of 25 to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Janssen Research Foundation, Beerse (Belgium)
OSTI Identifier:
7191467
Resource Type:
Journal Article
Journal Name:
J. Pharmacol. Exp. Ther.; (United States)
Additional Journal Information:
Journal Volume: 245:2
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; ENZYME INHIBITORS; BIOCHEMICAL REACTION KINETICS; RETINOIC ACID; METABOLISM; BIOLOGICAL HALF-LIFE; HAMSTERS; IN VITRO; IN VIVO; LIVER; RATS; TRACER TECHNIQUES; TRITIUM COMPOUNDS; ANIMALS; BODY; CARBOXYLIC ACID ESTERS; DIGESTIVE SYSTEM; ESTERS; GLANDS; ISOTOPE APPLICATIONS; KINETICS; LABELLED COMPOUNDS; MAMMALS; ORGANIC COMPOUNDS; ORGANS; REACTION KINETICS; RODENTS; VERTEBRATES; 550501* - Metabolism- Tracer Techniques

Citation Formats

Van Wauwe, J P, Coene, M C, Goossens, J, Van Nijen, G, Cools, W, and Lauwers, W. Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid. United States: N. p., 1988. Web.
Van Wauwe, J P, Coene, M C, Goossens, J, Van Nijen, G, Cools, W, & Lauwers, W. Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid. United States.
Van Wauwe, J P, Coene, M C, Goossens, J, Van Nijen, G, Cools, W, and Lauwers, W. Sun . "Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid". United States.
@article{osti_7191467,
title = {Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid},
author = {Van Wauwe, J P and Coene, M C and Goossens, J and Van Nijen, G and Cools, W and Lauwers, W},
abstractNote = {Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of (/sup 3/H)RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the (/sup 3/H)RA injection, the radioactivity extracted from the liver consisted of 25 to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.},
doi = {},
journal = {J. Pharmacol. Exp. Ther.; (United States)},
number = ,
volume = 245:2,
place = {United States},
year = {1988},
month = {5}
}