Inhibition and induction of microsomal enzymes in rat. A comparative study of four antimycotics: miconazole, econazole, clotrimazole and ketoconazole.

The interaction of four imidazole antimycotics clotrimazole, econazole, ketoconazole and miconazole with other drugs was studied in in vivo models known to reveal inhibition and induction of microsomal enzymes. In rats the duration of methohexital hypnosis and the prothrombin time prolongation induced by acenocoumarol were changed after oral administration of all four antimycotics. The oral ED50-values of miconazole, econazole and clotrimazole for prolongation of methohexital hypnosis in female rats (acute inhibiton of microsomal enzymes) were 3.55, 3.56 and 10.7 mg/kg. Ketoconazole, inhibited microsomal enzymes at the 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); the ED50 of clotrimazole for his activity was 14.9 mg/kg. The lowest effective dose of ketoconazole for extra-prolongation of the prothrombin time was 50 mg/kg, whereas the other antimycotics showed this effect at much lower doses. The implications of these results for the therapeutic use of these compounds are discussed and it is concluded that ketoconazole can be considered to be devoid of interaction with drugs, of which the intensity and duration of action strongly depends on their metabolic transformation rate in the liver.