Mosca P, Bonazzi P, Novelli G, Jezequel A M, Orlandi F
Br J Exp Pathol. 1985 Dec;66(6):737-42.
Ketoconazole (KC), a broad spectrum antifungal drug, has been recognized recently as a cause of hepatic injury. The mechanism of the adverse reaction remains unclear: a metabolic idiosincrasy has been suggested. However as a substituted imidazole, KC might be expected to interfere with the hepatic microsomal mixed function oxidases. Ethylmorphine N-demethylase (E-DM) and aniline hydroxylase (A-OH) activities were determined in rat liver microsomes in the presence of increasing amounts of KC. Both were inhibited in an exponential fashion. The E-DM inhibition was almost complete at concentrations greater than 250 microM and was of the mixed type. A much weaker effect was observed for A-OH. A significant inhibition of E-DM was also observed when KC was administered in vivo to rats either orally for 7 days at the dose of 100 mg/kg/day (P less than 0.02) or intraperitoneally for 4 days at the dose of 50 or 100 mg/kg day (P less than 0.01 or P less than 0.001 respectively). A-OH activity was significantly reduced (P less than 0.01) only after ip administration of 100 mg/kg/day of the drug for 4 days. Neither the amount of cytochrome P-450 nor NADPH cytochrome c reductase activity were affected at the doses considered. These data show that KC interferes with hepatic oxidative drug metabolism and suggest that this mechanism might be involved in the unwanted side effects of therapy with KC.
酮康唑（KC）是一种广谱抗真菌药物，最近已被确认为肝损伤的一个病因。不良反应的机制仍不清楚：有人提出这是一种代谢特异反应。然而，作为一种取代咪唑，预计KC可能会干扰肝微粒体混合功能氧化酶。在存在越来越多KC的情况下，测定了大鼠肝微粒体中的乙基吗啡N-脱甲基酶（E-DM）和苯胺羟化酶（A-OH）活性。两者均呈指数方式受到抑制。当浓度大于250 microM时，E-DM抑制几乎完全，且为混合型。观察到A-OH的作用要弱得多。当以100 mg/kg/天的剂量给大鼠口服KC 7天（P<0.02）或以50或100 mg/kg/天的剂量腹腔注射KC 4天（分别为P<0.01或P<0.001）时，也观察到E-DM受到显著抑制。仅在以100 mg/kg/天的剂量腹腔注射该药物4天后，A-OH活性才显著降低（P<0.01）。在所考虑的剂量下，细胞色素P-450的量和NADPH细胞色素c还原酶活性均未受到影响。这些数据表明KC会干扰肝脏的氧化药物代谢，并提示该机制可能与KC治疗的不良副作用有关。
