title: Liarozole fumarate inhibits the metabolism of 4-keto-all-trans-retinoic acid.
abstract: The metabolism of 4-keto-all-trans-retinoic-acid (4-keto-RA), a biologically active oxygenated metabolite of all-trans-retinoic (RA), has been examined. In vitro, incubation of [14C]4-keto-RA with hamster liver microsomes in the presence of NADPH produced two major radioactive metabolites which were more polar than the parent compound. Following isolation, appropriate derivatization and analysis by GC-MS, these compounds were tentatively identified as 2-hydroxy- and 3-hydroxy-4-ketoretinoic acid. Formation of both hydroxy-keto derivatives was suppressed by the imidazole-containing P450 inhibitor liarozole fumarate (IC50, 1.3 microM). In vitro, an i.v. injection of 4-keto-RA (20 micrograms) into rats was followed by rapid disappearance of the retinoid from plasma with a half-life of 7 min. Pretreatment with liarozole fumarate (40 mg/kg, -60 min) reduced the elimination rate of 4-keto-RA: it prolonged the plasma half-life of the retinoid to 12 min, without affecting its distribution volume. These results indicate the important role of the P450 enzyme system in the metabolism of 4-keto-RA both in vitro and in vivo. The inhibitory effect of liarozole fumarate on this metabolic process may contribute to the reported retinoid-mimetic activity of this drug.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Van Wauwe
authors.forename: M C
authors.initials: MC
authors.lastname: Coene
authors.forename: W
authors.initials: W
authors.lastname: Cools
authors.forename: J
authors.initials: J
authors.lastname: Goossens
authors.forename: W
authors.initials: W
authors.lastname: Lauwers
authors.forename: L
authors.initials: L
authors.lastname: Le Jeune
authors.forename: C
authors.initials: C
authors.lastname: Van Hove
authors.forename: G
authors.initials: G
authors.lastname: Van Nyen
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006224:Cricetinae; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D007093:Imidazoles; C002202:4-oxoretinoic acid; D014212:Tretinoin; C061121:liarozole