Ritter J K, Franklin M R
Toxicol Lett. 1987 Mar;36(1):51-9. doi: 10.1016/0378-4274(87)90040-3.
Three antimycotic N-substituted imidazoles, clotrimazole, tioconazole and miconazole, were able to induce hepatic microsomal cytochrome P-450 and monooxygenase reactions in both male and female hamsters to an extent similar to that seen with phenobarbital treatment. Imidazole treatment did not alter the cytochrome P-450 concentration, and ketoconazole treatment decreased it. Cytosolic sulfo- and glutathione transferases were not significantly altered by any imidazole. Induction of microsomal morphine glucuronosyltransferase activity by each compound generally paralleled the effect on cytochrome P-450 in females but induction was not evident in males. Clotrimazole treatment, in contrast to phenobarbital treatment, also caused a large induction of l-naphthol glucuronosyltransferase in females. The potential for antimycotic imidazoles to alter the hepatotoxicity of compounds will require consideration of the inductive changes in both Phase I and Phase II drug metabolizing enzymes in addition to their known inhibitory effects on Phase I oxidations. The inductive effects differ for each imidazole, and in the hamster model, depend upon the sex of the animal.
三种抗真菌的N-取代咪唑类药物，克霉唑、噻康唑和咪康唑，能够在雄性和雌性仓鼠中诱导肝微粒体细胞色素P-450和单加氧酶反应，其诱导程度与苯巴比妥治疗时相似。咪唑治疗并未改变细胞色素P-450的浓度，而酮康唑治疗使其降低。任何一种咪唑对胞质磺基转移酶和谷胱甘肽转移酶均无显著影响。每种化合物对微粒体吗啡葡糖醛酸基转移酶活性的诱导在雌性中通常与对细胞色素P-450的影响平行，但在雄性中诱导不明显。与苯巴比妥治疗不同，克霉唑治疗还能在雌性中大量诱导1-萘酚葡糖醛酸基转移酶。抗真菌咪唑类药物改变化合物肝毒性的可能性，除了其对I相氧化的已知抑制作用外，还需要考虑I相和II相药物代谢酶的诱导变化。每种咪唑的诱导作用不同，在仓鼠模型中，还取决于动物的性别。
