Influence of menstrual cycle on cytochrome P450 2A6 activity and cardiovascular effects of nicotine.
OBJECTIVE
The phase of the menstrual cycle has been reported to affect frequency of smoking, withdrawal symptoms, and the likelihood of smoking cessation in women. Cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Our objective was to evaluate the effect of the phase of the menstrual cycle on the activity of CYP2A6 and the cardiovascular effects of nicotine.


METHODS
Eleven healthy, nonsmoking women received a 30-minute combined infusion of deuterium-labeled nicotine and cotinine (0.5 microg . kg(-1) . min(-1) of each compound) during the midfollicular and midluteal phases of the menstrual cycle. Nicotine and cotinine pharmacokinetic parameters and plasma adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine responses were measured over time.


RESULTS
There were no biologically or statistically significant differences in the comparison of menstrual cycle phases with regard to the pharmacokinetics of nicotine and cotinine. Nicotine clearance was 1000 +/- 315 mL/min and 1047 +/- 271 mL/min in the follicular and luteal phases, respectively (geometric mean ratio, 1.06; 90% confidence interval, 0.87-1.29). Cotinine clearance was 44 +/- 20 mL/min and 55 +/- 42 mL/min in the follicular and luteal phases, respectively (geometric mean ratio, 1.13; 90% confidence interval, 0.90-1.41). Nicotine infusion increased blood pressure, heart rate, and epinephrine concentrations. There were no differences in catecholamine, ACTH, or hemodynamic responses to nicotine infusion between menstrual cycle phases, although norepinephrine concentrations were constantly higher in the luteal phase compared with the follicular phase.


CONCLUSIONS
CYP2A6 activity is not affected by menstrual cycle phase, and it is unlikely that menstrual cycle-related smoking habits of women are determined by changes in nicotine pharmacokinetics. The effects of nicotine on plasma ACTH and catecholamine levels and hemodynamic parameters are not altered by menstrual cycle phase in healthy, nonsmoking women.
Hukkanen
Janne
J
Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, CA 94143, USA.
Gourlay
Steven G
SG
Kenkare
Saraswati
S
Benowitz
Neal L
NL
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D003367:Cotinine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D065637:Cytochrome P-450 CYP2A6; D003903:Deuterium; D004837:Epinephrine / Q000097:blood; D004958:Estradiol / Q000097:blood; D005260:Female; D005498:Follicular Phase / Q000187:drug effects / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D008183:Luteal Phase / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009638:Norepinephrine / Q000097:blood; D011374:Progesterone / Q000097:blood
D002317:Cardiovascular Agents; D011374:Progesterone; D004958:Estradiol; D009538:Nicotine; D000324:Adrenocorticotropic Hormone; D003903:Deuterium; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D003367:Cotinine; D009638:Norepinephrine; D004837:Epinephrine