CYP2B6 Genotype Alters Abstinence Rates in a Bupropion Smoking Cessation Trial

Lee, AM; Jepson, Christopher; Hoffmann, E; Epstein, Leonard H.; Hawk, Larry W.; Lerman, Caryn; Tyndale, Rachel F.

doi:10.1016/j.biopsych.2006.10.005

Cited by 120 publications

(114 citation statements)

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“…CYP2B6*6 was detected in a haplotype assay using a twostep allele-specific polymerase chain reaction (PCR) as described previously [14]. Selected samples were sequenced according to a standard protocol with ABI PRISM Big Dye Terminator Cycle Sequencing Ready Reaction Kit and ABI 3700 DNA Analyzer (Applied Biosystems, Foster City, California, USA).…”

Section: Cyp2b6 Genotypingmentioning

confidence: 99%

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Qin

Zhang

Liu

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite, 4-hydroxybupropion, almost exclusively by CYP2B6.• Metamizole, a pyrazolone derivative with analgesic properties, was shown in an in vitro study to increase significantly the expression of CYP2B6 and bupropion hydroxylase activity.• The effect of metamizole on bupropion hydroxylation has not been investigated and drug interactions may occur between metamizole and bupropion. WHAT THIS PAPER ADDS• Oral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects.• Dosage adjustment of bupropion may be needed in patients when metamizole is concomitantly administered. AIMSThis study aimed to investigate the effect of metamizole on bupropion hydroxylation related to different CYP2B6 genotype groups in healthy volunteers. METHODSSixteen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6 and 4 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with metamizole 1500 mg day -1 (500 mg tablet taken three times daily) for 4 days. Serial blood samples were obtained up to 48 h after each bupropion dose. RESULTSAfter metamizole treatment relative to bupropion alone, the geometric mean ratios (GMRs) and 90% confidence interval (CI) of the AUC(0,•) ratio of 4-hydroxybupropion over bupropion were 1.99 (1.57, 2.55) for the CYP2B6*1/*1 group, 2.15 (1.53, 3.05) for the CYP2B6*1/*6 group and 1.86 (1.36, 2.57) for the CYP2B6*6/*6 group. The GMRs and 90% CI of bupropion were 0.695 (0.622, 0.774) for AUC(0,•) and 0.400 (0.353, 0.449) for Cmax, respectively. The corresponding values for 4-hydroxybupropion were 1.43 (1.28, 1.53) and 2.63 (2.07, 2.92). The t1/2 value was significantly increased for bupropion and decreased for 4-hydroxybupropion. The tmax values of bupropion and 4-hydroxybupropion were both significantly decreased. The mean percentage changes in pharmacokinetic parameters among the CYP2B6 genotype groups were not significantly different. CONCLUSIONSOral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects. Cautions should be taken when metamizole is co-administered with CYP2B6 substrate drugs.

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Section: Cyp2b6 Genotypingmentioning

confidence: 99%

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Qin

Zhang

Liu

et al. 2012

Brit J Clinical Pharma

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“…In rats, the inhibition of brain CYP2B activity through intracerebroventricular injection of a selective CYP2B inhibitor led to higher rates of acquisition of nicotine self-administration behavior but no difference in level of responding among dependent animals; this was performed without altering peripheral nicotine levels or metabolism (Garcia et al, 2015). It is possible that CYP2B6 variation within human brain may lead to altered central metabolism of nicotine, which may account for the observed differences in nicotine dependence (Riccardi et al, 2015) and cessation outcomes (Lee et al, 2007a), while having no effect on the level of consumption as observed here.…”

Section: Discussionmentioning

confidence: 99%

“…The CYP2B6*6 allele, a prevalent haplotype (~25% frequency in Whites (Rotger et al, 2007)) is associated with lower CYP2B6 hepatic protein levels (Al and slower CYP2B6-mediated metabolism of bupropion and efavirenz (reviewed in (Thorn et al, 2010)). In adult smokers, CYP2B6*6 was associated with lower abstinence rates in the placebo arm of a bupropion smoking cessation clinical trial; 15% of individuals with one or two copies of CYP2B6*6 achieved abstinence, compared to 32% of CYP2B6*1/*1 individuals (Lee et al, 2007a). In a separate study, the CYP2B6*6 allele was more frequent in nicotine dependent individuals compared to those that were not dependent (32% vs. 22%, respectively) (Riccardi et al, 2015).…”

Section: Introductionmentioning

confidence: 90%

“…Participants were grouped into CYP2A6 normal, intermediate, or slow nicotine metabolism groups based on the predicted metabolic impact of each CYP2A6 variant allele (Chenoweth et al, 2013). Participants were also genotyped for the CYP2B6*6 allele, using a haplotyping method described previously (Lee et al, 2007a;Mwenifumbo et al, 2005); individuals with the CYP2B6*1/ *1 genotype were grouped as normal metabolizers, while those with one or two copies of the CYP2B6*6 alleles were grouped as slow metabolizers. For genetic analyses, the sample was restricted to White ever-smokers in order to minimize possible effects of population stratification.…”

Section: Determination Of Cyp2a6 and Cyp2b6 Genotypementioning

confidence: 99%

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Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

Chenoweth

Sylvestre

Contreras

et al. 2016

Drug and Alcohol Dependence

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Background-Smoking is influenced by genetic factors including variation in CYP2A6 and CYP2B6, which encode nicotine-metabolizing enzymes. In early adolescence, CYP2A6 slow nicotine metabolism was associated with higher dependence acquisition, but reduced cigarette consumption. Here we extend this work by examining associations of CYP2A6 and CYP2B6 with tobacco dependence acquisition in a larger sample of smokers followed throughout adolescence.Methods-White participants from the Nicotine Dependence in Teens cohort that had ever inhaled (n=421) were followed frequently from age 12-18 years. Cox's proportional hazards models compared the risk of ICD-10 tobacco dependence acquisition (score 3+) for CYP2A6 and CYP2B6 metabolism groups. Early smoking experiences, as well as amount smoked at end of follow-up, was also computed. At age 24 (N=162), we assessed concordance between selfreported cigarette consumption and salivary cotinine.Results-In those who initiated inhalation during follow-up, CYP2A6 slow (vs. normal) metabolizers were at greater risk of dependence (hazards ratio (HR)=2.3; 95% CI=1.1, 4.8); CYP2B6 slow (vs. normal) metabolizers had non-significantly greater risk (HR=1.5; 95% CI=0.8, 2.6). Variation in CYP2A6 or CYP2B6 was not significantly associated with early smoking symptoms or cigarette consumption at end of follow-up. At age 24, neither gene was significantly associated with dependence status. Self-reported consumption was associated with salivary cotinine, a biomarker of tobacco exposure, acquired at age 24 (B=0.37; P<0.001). CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptConclusions-Our findings extend previous work indicating that slow nicotine metabolism mediated by CYP2A6, and perhaps CYP2B6, increases risk for tobacco dependence throughout adolescence.

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“…7 Other reports have suggested that genetic variation in nicotine-metabolizing enzymes (for example, CYP2A6 and CYP2B6) might also predict response to NRT. [24][25][26] Although pharmacogenetic data on varenicline are not yet available, emerging data from bupropion and NRT trials raise hopes that genetic tests may eventually help select more effective tobacco dependence treatments for individual smokers.…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment

et al. 2008

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We evaluated the cost-effectiveness of a range of smoking cessation drug treatments, including varenicline, transdermal nicotine (TN), bupropion and the use of a genetic test to choose between TN and bupropion. We performed Monte Carlo simulation with sensitivity analysis, informing analyses with published estimates of model parameters and current prices for genetic testing and smoking-cessation therapy. The primary outcomes were discounted life-years (LY) and lifetime tobacco-cessation treatment costs. In the base case, varenicline treatment was optimal with an ICER, compared to bupropion, of $2985/LY saved. In sensitivity analyses, varenicline was in all cases (and bupropion in most cases) admissible; only under favorable assumptions was the genetically tailored approach competitive. Our data suggest that an untailored approach of treatment with either bupropion or varenicline is a cost-effective form of tobacco dependence treatment, but a tailored approach for selecting between TN and bupropion can be cost-effective under plausible assumptions.

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CYP2B6 Genotype Alters Abstinence Rates in a Bupropion Smoking Cessation Trial

Cited by 120 publications

References 37 publications

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers

Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment

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