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  • Title: Induction potential of antifungals containing an imidazole or triazole moiety. Miconazole and ketoconazole, but not itraconazole are able to induce hepatic drug metabolizing enzymes of male rats at high doses.
    Author: Lavrijsen K, Van Houdt J, Thijs D, Meuldermans W, Heykants J.
    Journal: Biochem Pharmacol; 1986 Jun 01; 35(11):1867-78. PubMed ID: 3013201.
    Abstract:
    Male Wistar rats were dosed with miconazole, ketoconazole and itraconazole by gastric intubation once daily for up to 7 days. A dose- and time-dependent induction of the hepatic drug metabolizing enzyme system was observed for miconazole and ketoconazole, while itraconazole proved to be devoid of inductive properties even at the highest dose studied (160 mg/kg). No effect on drug metabolizing enzymes could be demonstrated for either drug at a dose level of 10 mg/kg, which is just above the antifungally active dose. At a dose of 40 mg/kg, miconazole, but not ketoconazole, significantly increased cytochrome P-450 content. At the highest dose of 160 mg/kg, both miconazole and ketoconazole increased the relative liver weight, the cytochrome P-450- and b5-content and NADPH-cyt c-reductase. Furthermore, miconazole, but not ketoconazole, increased specific microsomal aminopyrine and N,N-dimethylaniline N-demethylase activity, p-nitroanisole O-demethylase activity and UDP-glucuronyltransferase activity towards 4-nitrophenol while the specific aniline hydroxylase activity was unaffected. Ketoconazole at 160 mg/kg only induced O-demethylase activity and UDP-glucuronyltransferase activity, while it lowered the specific activities towards the other substrates. Miconazole was a relatively more potent inducer when compared to ketoconazole. Both drugs displayed biphasic effects on the mixed-function oxidase activities, which were lowered after acute administration (160 mg/kg, 1 hr before death) and were induced when determined after 23 hr had elapsed or after multiple dosage. Both drugs bound strongly to their respective induced cytochromes, giving rise to type II difference spectra, and inhibited the O-demethylase activity of the induced microsomes with an I50 of 5.2 microM for miconazole and 15.1 microM for ketoconazole. On the basis of a comparison of the enzymatic activities induced by both antimycotics with those induced by PB or 3-MC, it was concluded that miconazole behaved as a PB-type inducer, whereas ketoconazole did not belong to either category of inducers. A comparison of electrophoretograms of microsomes from different origins on SDS-PAGE revealed that miconazole increased the concentration of several proteins, whereas ketoconazole selectively induced a protein with Mr of 47,800. The protein pattern in the 50 kDa region of miconazole-induced microsomes resembled that of PB-microsomes qualitatively.
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