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 [ 14 C]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 ( ic 50 , 1.3μM). In vivo , an i.V. injection of 4-keto-RA (20 μg) 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.