CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion

Clin Pharmacol Ther. 2012 Dec;92(6):771-7. doi: 10.1038/clpt.2012.186. Epub 2012 Nov 14.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents, Second-Generation / metabolism*
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Black or African American
  • Bupropion / analogs & derivatives
  • Bupropion / metabolism*
  • Bupropion / therapeutic use*
  • Cytochrome P-450 CYP2B6
  • Double-Blind Method
  • Humans
  • Kinetics
  • Logistic Models
  • Odds Ratio
  • Oxidoreductases, N-Demethylating / metabolism*
  • Predictive Value of Tests
  • Smoking / drug therapy*
  • Smoking Cessation*
  • Treatment Outcome


  • Antidepressive Agents, Second-Generation
  • Bupropion
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating