1. ¹Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa
2. ²Centre for Addiction and Mental Health, University of Toronto, Toronto
3. ³Department of Pharmacology, University of Toronto, Toronto
4. ⁴Department of Oncology, Georgetown University, Washington, DC
5. ⁵Department of Medicine, Division of Clinical Pharmacology, University of California, San Francisco, San Francisco, Calif
6. ⁶Department of Psychiatry, Division of Clinical Pharmacology, University of California, San Francisco, San Francisco, Calif
7. ⁷Department of Biopharmaceutical Sciences, Division of Clinical Pharmacology, University of California, San Francisco, San Francisco

Correspondence: Caryn Lerman, PhD, University of Pennsylvania Transdisciplinary Tobacco Use Research Center, 3535 Market St, Suite 4100, Philadelphia, PA 19104. E-mail: clerman@mail.med.upenn.edu

^*This work was supported by a Transdisciplinary Tobacco Use Research Center Grant from the National Cancer Institute and the National Institute on Drug Abuse (P5084718); by the Abramson Cancer Center and Annenberg Public Policy Center (C.L.); by PHS grants DA02277, DA12393, and CA078703, as well as the University of California San Francisco Comprehensive Cancer Center (N.B.); and by a United States Public Health Service Research Grant (M01-RR0040) from the National Institutes of Health. R.T. is supported by the Centre for Addiction and Mental Health and a Canada Research Chair. Nicotine nasal spray (Nicotrol) was provided by Pharmacia, Helsingborg, Sweden. This work was also supported by funds from the Pennsylvania State Tobacco Settlement.

Received 6 October 2005; Accepted 8 February 2006; Published online 11 May 2006.

Abstract

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 (=-1.72, t₁₇₉=-3.31, P < .001), as well as more severe cravings for cigarettes after 1 week of treatment (=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.