Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking

Background: Nicotine establishes and maintains tobacco dependence. Individu als with generically deficient CYP2A6 nicotine metabolism are at lower risk to become smokers and, if dependent, will smoke fewer cigarettes, Hepatic CYP2A6 accounts for nicotine's low systemic bioavailability, precluding ora l nicotine replacement to treat dependence. Objective: We sought to determine whether CYP2A6 inhibition via oral methox salen decreases nicotine clearance, increases nicotine bioavailability, and decreases smoking. Methods: Two within-subject designs in healthy tobacco-dependent volunteers were conducted: a single-blind kinetic study (n = 17) of methoxsalen 30, 1 0, or 3.5 mg or placebo given with nicotine 4 mg orally to abstinent smoker s; and a double-blind randomized crossover study (n = 11) of methoxsalen 30 mg or placebo crossed with nicotine 4 mg given orally or placebo before 60 minutes' abstinence and 90 minutes' free smoking, Results: Placebo plus nicotine 4 mg orally increased the mean a-hour plasma nicotine level by 4 ng/mL over residual baseline nicotine level, whereas m ethoxsalen 10 or 30 mg plus nicotine increased it by 9 ng/mL (P < .01), dem onstrating in vivo inhibition of CYP2A6 nicotine metabolism. Methoxsalen 30 mg plus nicotine 4 mg given orally decreased breath carbon monoxide concen tration at the end of free smoking by 47% (4.6 versus 8.7 ppm; P < .01) and cigarettes smoked by 24% (3.1 versus 4.1, P < .01) compared with placebo p lus placebo. Conclusions: Methoxsalen inhibits nicotine first-pass metabolism of orally administered nicotine, and the combination directly reduces smoking in a la boratory setting. CYP2A6 inhibitors may have an important role in smoking c essation and tobacco exposure reduction.