Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity

Objective: The rate of nicotine metabolism, determined primarily by CYP2A6 activity, influences tobacco dependence and smoking-induced disease risk. The prevalence of CYP2A6 gene variants differs by race, with greater numbers in African Americans compared with Caucasians. We studied nicotine disposition kinetics and metabolism by the CYP2A6 genotype and enzymatic activity, as measured by the nicotine metabolite ratio (NMR), in African American smokers. Methods: Participants were administered intravenous infusions of deuterium-labeled nicotine and cotinine. Plasma and urine concentrations of nicotine and metabolites were measured and pharmacokinetic parameters were estimated. Results: Pharmacokinetic parameters and urine metabolite excretion data were analyzed by CYP2A6 genotype and by NMR. A number of gene variants were associated with markedly reduced nicotine and cotinine clearances. NMR was strongly correlated with nicotine (r=0.72) and cotinine (r=0.80) clearances. Participants with higher NMR excreted significantly greater nicotine C-oxidation and lower non-C-oxidation products compared with lower NMR participants. Conclusion: CYP2A6 genotype, NMR, and nicotine pharmacokinetic data may inform studies of individual differences in smoking behavior and biomarkers of nicotine exposure.

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