Ketoconazole And Aidi Kang The Azole Liver Toxicity Studies

Ketoconazole(KCZ) is an imidazole antifungal agent with a broad spectrum of activity against systemic and superficial mycoses. The hepatotoxicity of KCZ and its influences on some subtypes of CYP450 have been discovered both in clinic and animal experiments. Iodiconazole is a novel triazole antifungal agent with a more effective activity against systemic and superficial mycoses compared with KCZ due to the substitution of imidazole loop with triazole loop in structure. The mechanisms of the hepatotoxicty and influences on CYP450 of KCZ haven't been identified while Iodiconazole is still in preclinical stage and its toxicity has not been investigated. In this study, the effections of both agents on the serum biochemistry profiles, sulfhydryl groups contents in liver tissue, the activities of main subtypes of CYP450 and histological changes were compared both in male SD rats and in primary cultured rat hepatocytes and the potentisl mechanism(s) of their hepatotoxicity were also investigated in order to offer some toxicological information for reasonable application of KCZ in clinic and the development of Iodiconazole as a novel antifungal drug.In animal experiment, after the administration of Ketoconazole and Iodiconazole by gavage at 140, 280, 420μmol·kg^-1·d^-1 dosage for 7 days consistently, serum biochemistry parameters and sulfhydryl groups in liver tissue of male SD rats didn't change significantly. The activity of CYP2E1 didn't change greatly while the activities of CYP1A1, CYP1B1 increased and the activity of CYP3A decreased dose-dependently, respectively in Ketoconazole treated rats. However, the activities of CYP1A2 and CYP2B1 were inhibited in low dose group while induced in high dose group of Ketoconazole. The activities of CYP1A1, CYP1B1, CYP2B1 and CYP2E1 increased while the activities of CYP1A2, CYP3A decreased after induction with Iodiconazole. Both changes were significant and dose-dependent. In another test, Ketoconazole and Iodiconazole were administered to male SD rats by gavage at 420μmol·kg^-1·d^-1 for 1, 4, 7 days, respectively. Serum biochemistry parameters and sulfhydryl groups in liver tissue didn't change significantly except that alanine aminotransferase (ALT) increased significantly at 4 days after administration of KCZ. The activities of CYP1A1, CYP1B1,...