1. ¹Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Toronto, ON, Canada
2. ²Department of Psychiatry and Abramson Cancer Center, Transdisciplinary Tobacco Use Research Center, University of Pennsylvania, Philadelphia, PA, USA
3. ³Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, University of California, San Francisco, CA, USA
4. ⁴Departments of Medicine, Psychiatry and Biopharmaceutical Sciences, University of California, San Francisco, CA, USA

Correspondence: Dr RF Tyndale, Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Room 4326 Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: r.tyndale@utoronto.ca

Received 27 September 2005; Revised 10 November 2005; Accepted 5 December 2005; Published online 10 January 2006.

Abstract

We investigated the effect of slow metabolism of nicotine, predicted by CYP2A6 genotypes resulting in 50% activity, on baseline smoking behaviours and treatment variables in an open-label nicotine replacement therapy (NRT) clinical trial. Caucasian smokers with CYP2A6 slow vs normal metabolism had lower metabolic activity, indicated by the 3-hydroxycotinine/cotinine ratio (0.230.17 vs 0.450.22, P<0.01, respectively). CYP2A6 slow metabolizers also smoked fewer cigarettes per day compared to normal metabolizers (207 vs 2410, respectively, P<0.04). With nicotine patch use, slow metabolizers had higher nicotine plasma levels compared to normal metabolizers (22.84.6 vs 15.87.6 ng/ml, respectively, P=0.02) while using the same numbers of patches/week. With nicotine spray use, where like in smoking the nicotine intake can be easily adjusted to adapt to rates of metabolism, slow metabolizers achieved similar nicotine levels compared to normal metabolizers (5.84.1 vs 8.09.1 ng/ml, P=0.82), by using fewer doses of nicotine spray/day (4.83.6 vs 10.58.0, respectively, P<0.02). These findings indicate that CYP2A6 genotype influences smoking behaviour in a Caucasian treatment-seeking population and that CYP2A6 genotype affects plasma levels obtained from, and usage of, NRT.