Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation

Background Nicotine is metabolized to cotinine, and cotinine is metabolized to 3′‐hydroxycotinine (3‐HC) by the liver enzyme cytochrome P450 (CYP) 2A6. More rapid metabolism of nicotine may result in lower nicotine blood levels from nicotine replacement products and poorer smoking cessation outcomes. This study evaluated the utility of the 3‐HC/cotinine ratio as a predictor of the efficacy of nicotine replacement therapy as an aid for smoking cessation. Methods By use of an open‐label design, 480 treatment‐seeking smokers were randomly assigned to 8 weeks of transdermal nicotine or nicotine nasal spray use, plus behavioral group counseling. Assessments included demographics, smoking history, body mass index, and plasma nicotine, cotinine, and 3‐HC concentrations, as well as CYP2A6 genotypes. Smoking cessation was biochemically verified at the end of treatment and at 6‐month follow‐up. Results The rate of nicotine metabolism, as indicated by pretreatment 3‐HC/cotinine ratio derived from cigarette smoking, predicted the effectiveness of transdermal nicotine at both time points. The odds of abstinence were reduced by almost 30% with each increasing quartile of metabolite ratio (odds ratio, 0.72 [95% confidence interval, 0.57–0.90]; P=.005). Higher metabolite ratios also predicted lower nicotine concentrations (β=−1.72, t179=−3.31, P < .001), as well as more severe cravings for cigarettes after 1 week of treatment (β=0.32, t190=2.91, P=.004). The metabolite ratio did not predict cessation with use of nicotine nasal spray (odds ratio, 1.05 [95% confidence interval, 0.83–1.33]; P=.68). Conclusion The nicotine metabolite ratio might be useful in screening smokers to determine likely success with a standard dose of transdermal nicotine. Clinical Pharmacology & Therapeutics (2006) 79, 600–608; doi: 10.1016/j.clpt.2006.02.006