Comparison of In Vitro Stereoselective Metabolism of Bupropion in Human, Monkey, Rat, and Mouse Liver Microsomes
Background and Objectives
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 (CLint) 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.
The authors thank Brandon Gufford (Indiana University), Jennifer Sager (Gilead Sciences), Andrea Masters (Indiana University), and Zeruesenay Desta (Indiana University) and Sara Quinney (Indiana University) for their technical advice.
Participated in research design: CB, DK, RES, MVS. Conducted experiments: CB and DK. Performed data analysis: CB and DK. Wrote or contributed to the writing of the manuscript: CB, DK, RES, MVS.
Compliance with Ethical Standards
The studies reported in this publication were supported by a grant from the Charles Henry Leach II fund.
Conflict of interest
All the authors declare that they have no conflict of interest.
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