Franklin M R
Department of Pharmacology and Toxicology, University of Utah 84112, USA.
Drug Metab Dispos. 1995 Dec;23(12):1379-82.
The formation of cytochrome P450 metabolic-intermediate (MI) complexes from amine-containing drugs unrelated to macrolide antibiotics was investigated in hepatic microsomes from rifampicin-induced rabbits. Rifampicin treatment doubled the amount of total cytochrome P450 present. As evidenced by increased rates of erythromycin N-demethylation and MI complex formation from troleandomycin without increases in other isozyme selective oxidation reactions, the increase was predominately in the cytochrome P4503A subfamily. Fluoxetine, benzylamphetamine, propoxyphene, and norpropoxyphene formed MI complexes at rates similar to that for troleandomycin. Rates for 1-alpha-acetylmethadol and SKF 525A were 2- to 3-fold higher, and rates for the secondary amine derivatives of these two compounds, nor-1-alpha-acetylmethadol and SKF 8742A, were approximately 5-fold higher than with troleandomycin. For the SKF and acetylmethadol compounds, the rates were much higher in rifampicin-induced microsomes, compared with phenobarbital-induced microsomes. MI complex formation from benzylamphetamine was the reverse. The rate of MI complex formation from benzylamphetamine in phenobarbital-induced microsomes was similar to that from SKF 8742A and nor-1-alpha-acetylmethadol in microsomes from rabbits treated with the highest dose of rifampicin. Cytochrome P450 MI complex formation from all compounds was either low or absent from microsomes of vehicle-treated animals.
在利福平诱导的兔肝微粒体中，研究了与大环内酯类抗生素无关的含胺药物形成细胞色素P450代谢中间体（MI）复合物的情况。利福平处理使细胞色素P450总量增加了一倍。红霉素N-去甲基化速率和醋竹桃霉素MI复合物形成速率增加，而其他同工酶选择性氧化反应速率未增加，这表明增加主要发生在细胞色素P4503A亚家族中。氟西汀、苄基苯丙胺、丙氧芬和去甲丙氧芬形成MI复合物的速率与醋竹桃霉素相似。1-α-乙酰美沙多和SKF 525A的速率高出2至3倍，这两种化合物的仲胺衍生物去甲-1-α-乙酰美沙多和SKF 8742A的速率比醋竹桃霉素高出约5倍。对于SKF和美沙多化合物，与苯巴比妥诱导的微粒体相比，利福平诱导的微粒体中的速率要高得多。苄基苯丙胺的MI复合物形成情况则相反。苯巴比妥诱导的微粒体中苄基苯丙胺的MI复合物形成速率与用最高剂量利福平处理的兔微粒体中SKF 8742A和去甲-1-α-乙酰美沙多的速率相似。在溶媒处理动物的微粒体中，所有化合物的细胞色素P450 MI复合物形成要么很低，要么不存在。
