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Comparison of In Vitro Stereoselective Metabolism of Bupropion in Human, Monkey, Rat, and Mouse Liver Microsomes
- 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.
- Subjects :
- Male
Clinical chemistry
Pharmacology
030226 pharmacology & pharmacy
Rats, Sprague-Dawley
Mice
03 medical and health sciences
0302 clinical medicine
Species Specificity
Pharmacokinetics
biology.animal
mental disorders
medicine
Animals
Humans
Pharmacology (medical)
Bupropion
Dose-Response Relationship, Drug
biology
Chemistry
Marmoset
Callithrix
Hydroxybupropion
Haplorhini
Rats
Dose–response relationship
030220 oncology & carcinogenesis
Microsomes, Liver
Microsome
Antidepressive Agents, Second-Generation
Female
Drug metabolism
medicine.drug
Subjects
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