title: Stereoselective Glucuronidation of Bupropion Metabolites In Vitro and In Vivo.
abstract: Bupropion is a widely used antidepressant and smoking cessation aid in addition to being one of two US Food and Drug Administration-recommended probe substrates for evaluation of cytochrome P450 2B6 activity. Racemic bupropion undergoes oxidative and reductive metabolism, producing a complex profile of pharmacologically active metabolites with relatively little known about the mechanisms underlying their elimination. A liquid chromatography-tandem mass spectrometry assay was developed to simultaneously separate and detect glucuronide metabolites of (R,R)- and (S,S)-hydroxybupropion, (R,R)- and (S,S)-hydrobupropion (threo) and (S,R)- and (R,S)-hydrobupropion (erythro), in human urine and liver subcellular fractions to begin exploring mechanisms underlying enantioselective metabolism and elimination of bupropion metabolites. Human liver microsomal data revealed marked glucuronidation stereoselectivity [Cl(int), 11.4 versus 4.3 µl/min per milligram for the formation of (R,R)- and (S,S)-hydroxybupropion glucuronide; and Cl(max), 7.7 versus 1.1 µl/min per milligram for the formation of (R,R)- and (S,S)-hydrobupropion glucuronide], in concurrence with observed enantioselective urinary elimination of bupropion glucuronide conjugates. Approximately 10% of the administered bupropion dose was recovered in the urine as metabolites with glucuronide metabolites, accounting for approximately 40%, 15%, and 7% of the total excreted hydroxybupropion, erythro-hydrobupropion, and threo-hydrobupropion, respectively. Elimination pathways were further characterized using an expressed UDP-glucuronosyl transferase (UGT) panel with bupropion enantiomers (both individual and racemic) as substrates. UGT2B7 catalyzed the stereoselective formation of glucuronides of hydroxybupropion, (S,S)-hydrobupropion, (S,R)- and (R,S)-hydrobupropion; UGT1A9 catalyzed the formation of (R,R)-hydrobupropion glucuronide. These data systematically describe the metabolic pathways underlying bupropion metabolite disposition and significantly expand our knowledge of potential contributors to the interindividual and intraindividual variability in therapeutic and toxic effects of bupropion in humans.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Brandon T
authors.initials: BT
authors.lastname: Gufford
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Jessica Bo Li
authors.initials: JB
authors.lastname: Lu
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Ingrid F
authors.initials: IF
authors.lastname: Metzger
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology Indiana University School of Medicine, Indianapolis, Indiana zdesta@iu.edu.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
mesh_terms: D016642:Bupropion / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020719:Glucuronides / Q000737:chemistry* / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008297:Male; D010865:Pilot Projects; D013237:Stereoisomerism
chemical_list: D020719:Glucuronides; D016642:Bupropion; D014453:Glucuronosyltransferase