Effects of nicotine on cytochrome P450 2A6 and 2E1 activities.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone. • Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity. • The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS • This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing. • High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates. • The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMS Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODS The study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTS There was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference −9.7, −0.6, P= 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONS CYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown. [ABSTRACT FROM AUTHOR]