Morais J A, Wagner J G
Biopharm Drug Dispos. 1984 Oct-Dec;5(4):357-76. doi: 10.1002/bdd.2510050407.
The use of isolated rat hepatocytes in studies of drug metabolism has become well documented in the past few years. However, in part because of modelling difficulties due to the simultaneously occurring substrate transferring processes, its predictability of in vivo situations has not been emphasized. Much controversy surrounds the metabolism of phenytoin (5,5-diphenylhydantoin), a widely used anticonvulsant, and an appropriate pharmacokinetic model to describe the disposition of this drug still lacks general acceptance. In the present study, metabolism of phenytoin in the isolated rat hepatocyte system was followed by assaying either the unchanged drug or the pooled metabolites in both the suspending medium and the cells. A model was developed which can describe the time course of the different species sampled. Inhibition of biotransformation by the major metabolic product [5-(p-hydroxyphenyl)-5-phenylhydantoin or p-HPPH] and the uptake and release of the latter were also studied, in order to elucidate the role of product inhibition in determining the dose-dependent pharmacokinetic behaviour of the drug. The results obtained strongly suggest that only concentrations of p-HPPH higher than the ones attained by phenytoin biotransformation alone can significantly inhibit the main enzymatic reaction.
在过去几年中，使用分离的大鼠肝细胞进行药物代谢研究已有充分的文献记载。然而，部分由于同时发生的底物转运过程导致建模困难，其对体内情况的预测性尚未得到重视。苯妥英（5,5 - 二苯基乙内酰脲）是一种广泛使用的抗惊厥药，围绕其代谢存在诸多争议，且描述该药物处置的合适药代动力学模型仍未得到普遍认可。在本研究中，通过测定悬浮介质和细胞中未变化的药物或汇总的代谢产物，跟踪苯妥英在分离的大鼠肝细胞系统中的代谢情况。建立了一个模型，该模型可以描述所采集的不同物种的时间进程。还研究了主要代谢产物[5 - （对羟基苯基） - 5 - 苯基乙内酰脲或对羟基苯基苯妥英（p - HPPH）]对生物转化的抑制作用以及后者的摄取和释放，以阐明产物抑制在确定该药物剂量依赖性药代动力学行为中的作用。所获得的结果强烈表明，只有高于仅由苯妥英生物转化所达到的浓度的对羟基苯基苯妥英才能显著抑制主要酶促反应。
