Influence of menstrual cycle on cytochrome P450 2A6 activity and cardiovascular effects of nicotine

Clin Pharmacol Ther. 2005 Mar;77(3):159-69. doi: 10.1016/j.clpt.2004.10.012.


Background and objectives: 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.

Method: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Adult
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Blood Pressure / drug effects
  • Cardiovascular Agents / pharmacology*
  • Clinical Trials as Topic
  • Cotinine / administration & dosage
  • Cotinine / blood
  • Cotinine / pharmacokinetics
  • Cytochrome P-450 CYP2A6
  • Deuterium
  • Epinephrine / blood
  • Estradiol / blood
  • Female
  • Follicular Phase / drug effects
  • Follicular Phase / metabolism*
  • Heart Rate / drug effects
  • Heart Rate / physiology
  • Humans
  • Infusions, Intravenous
  • Luteal Phase / drug effects
  • Luteal Phase / metabolism*
  • Mixed Function Oxygenases / metabolism*
  • Nicotine / administration & dosage
  • Nicotine / blood
  • Nicotine / pharmacokinetics*
  • Norepinephrine / blood
  • Progesterone / blood


  • Cardiovascular Agents
  • Progesterone
  • Estradiol
  • Nicotine
  • Adrenocorticotropic Hormone
  • Deuterium
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6
  • Cotinine
  • Norepinephrine
  • Epinephrine