Cho A K, Hiramatsu M, Schmitz D A, Landaw E M, Chang A S, Ramamurthy S, Jenden D J
Department of Pharmacology, University of California, Los Angeles, School of Medicine 90024-1735.
Drug Metab Dispos. 1993 Jan-Feb;21(1):125-32.
The pharmacokinetics of three phencyclidine analogs--phenylcyclohexyl-diethylamine (PCDE), phenylcyclohexylethylamine (PCE), and phenylcyclohexylamine (PCA)--were determined in rats after intravenous administration of each drug. Because PCE and PCA are major metabolites of PCDE, their plasma levels were also measured after administration of PCDE. Similarly, PCA concentrations was determined after administration of PCE. The data were combined and analyzed by nonlinear regression procedures using compartmental and noncompartmental models to determine the kinetic parameters of PCDE metabolism. The object was to estimate the kinetic constants for the metabolic sequence, PCDE to PCE to PCA. A 6-compartment model (two pools for each analyte) that included saturable components for the conversion of PCDE to PCE and PCE to PCA gave the best fit to the combined data. Despite large uncertainties for some microparameters, useful estimates were obtained for clearances, distribution volumes, and fraction of PCDE or PCE converted to PCE and PCA in vivo under nonsaturating conditions. The estimated fraction of PCDE converted to PCA and the apparent Km value for the conversion of PCDE to PCE were comparable to values obtained in vitro with microsomal preparations, suggesting that metabolic studies in vitro provide reasonable predictors of the biotransformation process in vivo for this class of compounds.
在给大鼠静脉注射三种苯环己哌啶类似物——苯基环己基二乙胺（PCDE）、苯基环己乙胺（PCE）和苯基环己胺（PCA）后，测定了它们的药代动力学。由于PCE和PCA是PCDE的主要代谢产物，在给予PCDE后也测量了它们的血浆水平。同样，在给予PCE后测定了PCA的浓度。使用房室模型和非房室模型，通过非线性回归程序对数据进行合并和分析，以确定PCDE代谢的动力学参数。目的是估计代谢序列PCDE→PCE→PCA的动力学常数。一个六房室模型（每种分析物有两个池），其中包括PCDE转化为PCE以及PCE转化为PCA的饱和成分，对合并后的数据拟合效果最佳。尽管某些微观参数存在较大不确定性，但在非饱和条件下，仍获得了体内清除率、分布容积以及PCDE或PCE转化为PCE和PCA的分数的有用估计值。PCDE转化为PCA的估计分数以及PCDE转化为PCE的表观Km值与用微粒体制剂在体外获得的值相当，这表明体外代谢研究为这类化合物在体内的生物转化过程提供了合理的预测指标。
