title: Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes.
abstract: Bupropion is used clinically to treat depression and to promote smoking cessation. It is metabolized by CYP2B6 to its active metabolite hydroxybupropion, yet alterations in CYP2B6 activity have little impact on bupropion plasma levels. Furthermore, less than 10% of a bupropion dose is excreted as urinary bupropion and its characterized metabolites hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, suggesting that alternative metabolic pathways may exist. In vitro data suggested CYP2C19 could metabolize bupropion. The current study investigated the impact of functional CYP2C19 genetic variants on bupropion pharmacokinetics and treatment outcomes. In 42 healthy volunteers, CYP2C19*2 (a reduced activity allele) was associated with higher bupropion area under the plasma concentration-time curve (AUC), but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670 hours⋅ng/ml in individuals with and without CYP2C19*2, respectively (P = 0.017). CYP2C19*2 was also associated with higher threohydrobupropion and erythrohydrobupropion AUC (P < 0.005). Adjusting for CYP2B6 genotype did not alter these associations, and CYP2C19 variants did not alter the utility of the hydroxybupropion/bupropion ratio as a measure of CYP2B6 activity. Finally, in a clinical trial of 540 smokers, CYP2C19 genotype was not associated with smoking cessation outcomes, supporting the hypothesis that bupropion response is mediated by hydroxybupropion, which is not altered by CYP2C19. In conclusion, our study reports the first in vivo evidence that reduced CYP2C19 activity significantly increases the steady-state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion. These pharmacokinetic changes were not associated with differences in bupropion's ability to promote smoking cessation in smokers, but may influence the side effects and toxicity associated with bupropion.
authors.affiliation: Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.).
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.affiliation: Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.).
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.).
authors.forename: Lisa Sanderson
authors.initials: LS
authors.lastname: Cox
authors.affiliation: Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.).
authors.forename: Jasjit S
authors.initials: JS
authors.lastname: Ahluwalia
authors.affiliation: Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.).
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Departments of Pharmacology and Toxicology (A.Z.X.Z., Q.Z., R.F.T.) and Department of Psychiatry (R.F.T.), University of Toronto, Ontario, Canada; Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Kansas City, Kansas (L.S.C.); Department of Medicine and Center for Health Equity, University of Minnesota Medical School, Minneapolis, Minnesota (J.S.A.); Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Bioengineering & Therapeutic Sciences, University of California, San Francisco, California (N.L.B.); and Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, Ontario, Canada (R.F.T.) r.tyndale@utoronto.ca.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D019540:Area Under Curve; D016642:Bupropion / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D010919:Placebos; D016540:Smoking Cessation / Q000379:methods*
chemical_list: D010919:Placebos; D016642:Bupropion; D065731:Cytochrome P-450 CYP2C19