CYTOCHROME-P450 ISOZYMES AND ANTIEPILEPTIC DRUG-INTERACTIONS
CYTOCHROME-P450 ISOZYMES AND ANTIEPILEPTIC DRUG-INTERACTIONS
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DOI：
10.1111/j.1528-1157.1995.tb06007.x
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发表时间：
1995-01-01
期刊：
影响因子：
5.6
通讯作者：
LEVY, RH
中科院分区：
文献类型：
--
作者：
LEVY, RH
最近的研究发现，个别异构体的细胞色素P450参与代谢的苯妥英（PHT）和卡马西平（CBZ）的抑制为基础的相互作用的预测成为可能。PHT主要通过羟基化为p-HPPH消除，该反应主要由CYP 2C 9催化，其次由CYP 2C 19（S-美芬妥英羟化酶）催化。采用CYP 2C 9的两种探针S-华法林酸甲苯磺丁脲，将异构体特异性原则（由相同异构体代谢的药物应表现出与相同抑制剂的相互作用）应用于PHT与17种抑制剂的相互作用。17种相互作用中的11种（磺胺苯吡唑、保泰松、氟康唑、阿扎丙宗、复方新诺明、丙氧芬、咪康唑、胺碘酮、双硫仑、甲硝唑和司替戊醇）可通过抑制CYP 2C 9解释，其余相互作用（非氨酯、奥美拉唑、西咪替丁、氟西汀、丙咪嗪和地西泮）可归因于抑制CYP 2C 19。对于CBZ，利用化学抑制剂、免疫抑制、肝库相关性和表达酶进行的研究确定，CYP 3A 4是催化CBZ-10，11-环氧化物形成的主要酶。这解释了CBZ与红霉素的显著相互作用。醋竹桃霉素和其它大环内酯类抗生素（克拉霉素、交沙霉素、氟霉素和桥辛霉素）。解释CBZ与其他抑制剂的相互作用的工作正在进行中。文献中未包含其他主要抗癫痫药物代谢相关亚型的其他信息。
Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phenytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition-based interactions possible. PHT is eliminated principally by hydroxylation to p-HPPH, a reaction catalyzed primarily by CYP2C9 and secondarily by CYP2C19 (S-mephenytoin hydroxylase). The principle of isoform specificity (drugs metabolized by the same isoform should exhibit interactions with the same inhibitors) was applied to the interactions of PHT with 17 inhibitors using two probes for CYP2C9, S-warfarin acid tolbutamide. Eleven of 17 interactions (sulfaphenazole, phenylbutazone, fluconazole, azapropazone, cotrimoxazole, propoxyphene, miconazole, amiodarone, disulfiram, metronidazole, and stiripentol) could be explained by inhibition of CYP2C9, The remaining interactions (felbamate, omeprazole, cimetidine, fluoxetine, imipramine, and diazepam) were attributed to inhibition of CYP2C19. For CBZ, studies utilizing chemical inhibitors, immunoinhibition, liver bank correlations, and expressed enzymes established that CYP3A4 is the main enzyme catalyzing formation of CBZ-10,11-epoxide. This explains the pronounced interactions of CBZ with erythromycin. troleandomycin, and other macrolide antibiotics (clarithromycin, josamycin, flurythromycin, and ponsinomycin). Work is in progress to explain the interactions of CBZ with other inhibitors. The literature contains no other information on isoforms involved in the metabolism of other major antiepileptic drugs.