title: CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion.
abstract: Bupropion is indicated to promote smoking cessation. Animal studies suggest that the pharmacologic activity of bupropion can be mediated by its major metabolite, hydroxybupropion. We measured plasma bupropion and its metabolite levels in a double-blind, placebo controlled, randomized smoking-cessation trial. Among the treatment-adherent individuals, higher hydroxybupropion concentrations (per μg/ml) resulted in better smoking-cessation outcomes (week 3, 7, and 26 odds ratio (OR) = 2.82, 2.96, and 2.37, respectively, P = 0.005-0.040); this was not observed with bupropion levels (OR = 1.00-1.03, P = 0.59-0.90). Genetic variation in CYP2B6, the enzyme that metabolizes bupropion to hydroxybupropion, was identified as a significant source of variability in hydroxybupropion formation. Our data indicate that hydroxybupropion contributes to the pharmacologic effects of bupropion for smoking cessation, and that variability in response to bupropion treatment is related to variability in CYP2B6-mediated hydroxybupropion formation. These findings suggest that dosing of bupropion to achieve a hydroxybupropion level of 0.7 μg/ml or increasing bupropion dose for CYP2B6 slow metabolizers could improve bupropion's cessation outcomes.
authors.affiliation: Center for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A Z X
authors.initials: AZ
authors.lastname: Zhu
authors.forename: L S
authors.initials: LS
authors.lastname: Cox
authors.forename: N
authors.initials: N
authors.lastname: Nollen
authors.forename: B
authors.initials: B
authors.lastname: Faseru
authors.forename: K S
authors.initials: KS
authors.lastname: Okuyemi
authors.forename: J S
authors.initials: JS
authors.lastname: Ahluwalia
authors.forename: N L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: R F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D001741:Black or African American; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D016642:Bupropion / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use*; D065702:Cytochrome P-450 CYP2B6; D004311:Double-Blind Method; D006801:Humans; D007700:Kinetics; D016015:Logistic Models; D016017:Odds Ratio; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011237:Predictive Value of Tests; D012907:Smoking / Q000188:drug therapy*; D016540:Smoking Cessation; D016896:Treatment Outcome
chemical_list: D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating