Pharmacokinetic Candidate Genes

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Studies have examined the role of variability in nicotine metabolism on treatment outcome after NRT. Treatment seeking smokers who were slow metabolizers (carriers of one null allele or two reduced activity alleles of the CYP2A6 gene) had significantly greater levels of plasma nicotine from the nicotine patch than normal metabolizers, despite equivalent rates of patch usage between both groups (Malaiyandi et al, 2006). In addition, fast metabolizers used the nicotine nasal spray more to obtain equal levels of plasma nicotine, compared to slow metaboliz-ers (Malaiyandi et al, 2006). In a separate trial, the rate of nicotine metabolism estimated using the phenotypic marker of CYP2A6 activity (3-hydroxycotinine/cotinine or nicotine metabolite ratio; NMR) predicted quitting success using the nicotine patch (Lerman et al, 2006b). Among individuals who used the nicotine patch, there was a 30% drop in the odds of remaining abstinent with each increasing quartile of the metabolite ratio (measured in quartiles) (Lerman et al, 2006b). There was no association of the nicotine metabolite ratio with smoking cessation in the nasal spray arm of this study, which may be explained by the greater variability in nasal spray use (Lerman et al, 2006b). Further, the CYP2A6 genotype data from this trial (Malaiyandi et al, 2006) indicated that the normal metabolizers had significantly greater usage of the nasal spray than the slow metabolizers, suggesting that this variability in use is related to metabolism rate. The association of nicotine metabolism rate and smoking cessation was replicated in an open-label nicotine patch study with participants in the first quartile for nicotine metabolite ratio (slow metabolizers) more likely to be abstinent vs. those in the other three quartiles (Schnoll et al, 2009). The nicotine metabolite ratio also predicted abstinence at 6-month follow-up, indicating that nicotine metabolism rate may influence quitting success independent of treatment (Lerman et al, 2006b). There was no effect of CYP2B6 genotype on quit rates after NRT (Lee et al, 2007b).

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