INHIBITION AND INDUCTION OF MICROSOMAL-ENZYMES IN THE RAT - A COMPARATIVE-STUDY OF 4 ANTI-MYCOTICS - MICONAZOLE, ECONAZOLE, CLOTRIMAZOLE AND KETOCONAZOLE

Abstract

The interaction of 4 imidazole antimycotics, clotrimazole, econazole, ketoconazole and miconazole, with other drugs was studied in in vivo models which reveal inhibition and induction of microsomal enzymes. In rats the duration of methohexital hypnosis and prothrombin time prolongation induced by acenocoumarol were changed after oral administration of all 4 antimycotics. Oral ED50 values of miconazole, econazole and clotrimazole for prolongation of methohexital hypnosis in female rats (acute inhibition of microsomal enzymes) were 3.55, 3.56 and 10.7 mg/kg, respectively. Ketoconazole inhibited microsomal enzymes at oral ED50 of 30.4 mg/kg in female and 97.0 mg/kg in male rats. After subchronic treatment only clotrimazole reduced the hypnosis time below control values (induction of microsomal enzymes); ED50 of clotrimazole for this activity was 14.9 mg/kg. The lowest effective dose of ketoconazole for extraprolongation of the prothrombin time was 50 mg/kg; the other antimycotics showed this effect at lower doses. The implications of these results for the therapeutic use of these compounds were discussed. Ketoconazole was considered to be devoid of interaction with drugs, of which the intensity and duration of action strongly depended on their metabolic transformation rate in the liver.