Bhattacharya Chandrali, Kirby Danielle, Van Stipdonk Michael, Stratford Robert E
Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA, 15282, USA.
Department of Pharmacy Practice, Purdue University, Indianapolis, IN, 46202, USA.
Eur J Drug Metab Pharmacokinet. 2019 Apr;44(2):261-274. doi: 10.1007/s13318-018-0516-4.
Bupropion is an atypical antidepressant and smoking cessation aid associated with wide intersubject variability. This study compared the formation kinetics of three phase I metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion) in human, marmoset, rat, and mouse liver microsomes. The objective was to establish suitability and limitations for subsequent use of nonclinical species to model bupropion central nervous system (CNS) disposition in humans.
Hepatic microsomal incubations were conducted separately for the R- and S-bupropion enantiomers, and the formation of enantiomer-specific metabolites was determined using LC-MS/MS. Intrinsic formation clearance (CL) of metabolites across the four species was determined from the formation rate versus substrate concentration relationship.
The total clearance of S-bupropion was higher than that of R-bupropion in monkey and human liver microsomes. The contribution of hydroxybupropion to the total racemic bupropion clearance was 38%, 62%, 17%, and 96% in human, monkey, rat, and mouse, respectively. In the same species order, threohydrobupropion contributed 53%, 23%, 17%, and 3%, and erythrohydrobupropion contributed 9%, 14%, 66%, and 1.3%, respectively, to racemic bupropion clearance.
The results demonstrate that phase I metabolism in monkeys best approximates that observed in humans, and support the preferred use of this species to investigate possible pharmacokinetic factors that influence the CNS disposition of bupropion and contribute to its high intersubject variability.
安非他酮是一种非典型抗抑郁药及戒烟辅助药物，个体间差异较大。本研究比较了人、狨猴、大鼠和小鼠肝微粒体中三种Ⅰ相代谢物（羟基安非他酮、苏式羟基安非他酮和赤式羟基安非他酮）的生成动力学。目的是确定非临床物种用于模拟安非他酮在人体中枢神经系统（CNS）处置情况的适用性和局限性。
分别对R-和S-安非他酮对映体进行肝微粒体孵育，并使用液相色谱-串联质谱法测定对映体特异性代谢物的生成。根据生成速率与底物浓度的关系确定四种物种中代谢物的内在生成清除率（CL）。
在猴和人肝微粒体中，S-安非他酮的总清除率高于R-安非他酮。羟基安非他酮对总外消旋安非他酮清除率的贡献在人、猴、大鼠和小鼠中分别为38%、62%、17%和96%。在相同物种顺序中，苏式羟基安非他酮对外消旋安非他酮清除率的贡献分别为53%、23%、17%和3%，赤式羟基安非他酮的贡献分别为9%、14%、66%和1.3%。
结果表明，猴的Ⅰ相代谢最接近人类观察到的情况，并支持优先使用该物种来研究可能影响安非他酮CNS处置并导致其个体间差异较大的药代动力学因素。
