Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women

<(Background and objectives)under bar>: The activity of the human cytochrom e P450 CYP1A2 is decreased by female sex hormones during pregnancy or treat ment with oral contraceptives. However, the influence of menstrual cycle on CYP1A2 activity is not clear. <(Methods)under bar>: CYP1A2 activity was mo nitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (me an +/- SD) 27.8 +/- 3.8 years, body mass index 23.8 +/- 3.8 kg x m(-2)) usi ng the specific substrate caffeine (mean doses 149 mg). After a run-in peri od started one week prior to expected onset of menses, daily saliva samples were taken 7.3 +/- 0.7 hours after caffeine intake throughout the cycle, a nd caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. <(Results)under bar>: Initial (da y 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body we ight (coefficient of variation (CV) 48%). The ratio of caffeine clearance f or the luteal (day -9 to -4 prior to onset of the next menses) to the folli cular phase (days 5 - 10) was (n = 13, point estimate) 1.03 (90% CI 0.95 - 1.12), indicating that there was no difference in CYP1A2 activity between t hese cycle phases. The median intraindividual CV in ovulatory cycles (n = 1 3) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. <(Concl usions)under bar>: A dose adaptation according to the phase of menstrual cy cle based on pharmacokinetics is not required for CYP1A2 substrates.