Original ArticleCYP2B6 Genotype Alters Abstinence Rates in a Bupropion Smoking Cessation Trial
Section snippets
Participants
Participants were enrolled from April 1999 to October 2001 at Georgetown University (Washington, DC) and State University of New York (SUNY) Buffalo (New York). Recruitment, demographics, and the protocol have been reported in detail elsewhere (Lerman et al 2002, Lerman et al 2006). A total of 555 participants enrolled in the pharmacogenetic trial, of whom 423 were successfully genotyped; the rest had insufficient DNA remaining for this analysis. Of the 423 for whom CYP2B6 genotyping was
Results
In our sample, 423 participants were successfully genotyped, including 342 Caucasians. The CYP2B6*9 allele was not found. The Caucasian genotype frequencies were CYP2B6*1/*1 (52.3%), CYP2B6*1/*6 (36.3%), CYP2B6*6/*6 (6.7%), CYP2B6*1/*4 (4.1%), and CYP2B6*4/*6 (.6%). The Caucasian CYP2B6*6 and CYP2B6*4 allele frequencies were 25.2% and 2.3%, respectively (n = 342 total); both alleles were in Hardy-Weinberg equilibrium (p = .96 and p = .53, respectively). Smokers with a CYP2B6*1/*4 genotype,
Discussion
This study illustrates the importance of investigating genetic variation in drug-metabolizing enzymes to predict smoking cessation and therapeutic response to bupropion. Without investigating CYP2B6 genetics, the overall effect on abstinence of bupropion is modest. However, when CYP2B6 genotype is incorporated, bupropion is significantly more efficacious than placebo for ∼45% of the population (those in the CYP2B6*6 group) but not in the remaining ∼55% (those in the CYP2B6*1 group). At EOT, the
References (43)
- et al.
Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: A preliminary study
Psychiatry Res
(2004) - et al.
Multiple forms of human P450 expressed in Saccharomyces cerevisiaeSystematic characterization and comparison with those of the rat
Biochem Pharmacol
(1996) - et al.
Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain
Neuropharmacology
(2003) - et al.
Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens
Biochem Biophys Res Commun
(2004) - et al.
An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles
Biochem Biophys Res Commun
(2002) - et al.
Haplotype structure and allele frequencies of CYP2B6 in a Korean population
Drug Metab Dispos
(2004) - et al.
Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors
Mol Pharmacol
(2004) - et al.
Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity
Drug Metab Dispos
(2000) - et al.
Human CYP2B6: Expression, inducibility and catalytic activities
Pharmacogenetics
(1999) - et al.
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs. sustained-release bupropion and placebo for smoking cessation: A randomized controlled trial
JAMA
(2006)
The use of long PCR to confirm three common alleles at the CYP2A6 locus and the relationship between genotype and smoking habit
Ann Hum Genet
Pharmacogenetics of efavirenz and central nervous system side effects: An Adult AIDS Clinical Trials Group study
AIDS
Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes
Pharmacogenetics
Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19
Pharmacogenetics
Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers
J Clin Pharmacol
Antidepressants for smoking cessation
Cochrane Database Syst Rev
A comparison of sustained-release bupropion and placebo for smoking cessation
N Engl J Med
Identification of CYP2B6 sequence variants by use of multiplex PCR with allele-specific genotyping
Clin Chem
Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations
Clin Ther
Functional characterization of cytochrome P450 2B6 allelic variants
Drug Metab Dispos
A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation
N Engl J Med
Cited by (116)
New medications development for smoking cessation
2023, Addiction NeuroscienceFate of drug-metabolizing enzymes in neurological diseases: Challenges and strategies
2022, Biochemistry of Drug Metabolizing Enzymes: Trends and ChallengesNicotine Dependence: Current Treatments and Future Directions
2019, Abeloff’s Clinical OncologyPharmacogenetics and smoking cessation
2019, Neuroscience of Nicotine: Mechanisms and TreatmentCytochrome P450 in Pharmacogenetics: An Update
2018, Advances in PharmacologyCitation Excerpt :CYP2B6*6 has been associated with reduced metabolism of bupropion, a prodrug which is activated by CYP2B6. The effect of CYP2B6*6 allele on the efficacy of bupropion in smoking cessation has been shown in some, but not all, studies (Chenoweth & Tyndale, 2017; Lee et al., 2007; Zhu et al., 2012). Pharmacokinetics of several other CYP2B6 substrates, such as cyclophosphamide, methadone, and nevirapine, have been reported to be influenced by CYP2B6 genotype, but evidence regarding them is not yet conclusive (Zanger & Klein, 2013).
Pharmacogenetic Optimization of Smoking Cessation Treatment
2017, Trends in Pharmacological SciencesCitation Excerpt :In Caucasian smokers, end-of-treatment quit rates on bupropion did not differ between individuals with no copies of CYP2B6*6 versus those with one to two copies of CYP2B6*6 (31% versus 33%, respectively; P = 0.84). However, bupropion and hydroxybupropion levels were not assessed in this study; thus, it is not possible to determine treatment adherence [40]. In verified treatment-adherent African-American light smokers (fewer than ten cigarettes/day) randomized to bupropion, slow CYP2B6 metabolizers (including those with the CYP2B6*6 haplotype) had lower plasma hydroxybupropion levels versus normal metabolizers; lower hydroxybupropion levels, in turn, were associated with poorer bupropion-assisted cessation [41].