Back to Search Start Over

Comparison of In Vitro Stereoselective Metabolism of Bupropion in Human, Monkey, Rat, and Mouse Liver Microsomes

Authors :
Chandrali Bhattacharya
Robert E. Stratford
Michael J. Van Stipdonk
Danielle Kirby
Source :
European Journal of Drug Metabolism and Pharmacokinetics. 44:261-274
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

Abstract

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.

Details

ISSN :
21070180 and 03787966
Volume :
44
Database :
OpenAIRE
Journal :
European Journal of Drug Metabolism and Pharmacokinetics
Accession number :
edsair.doi.dedup.....deab685db2fae3e7d8866341d289cb94
Full Text :
https://doi.org/10.1007/s13318-018-0516-4