Variability of endogenous cortisol 6β-hydroxylation clearance as index of in vivo CYP3A activity during menstrual cycle in healthy women

H Shibasaki-Hirano, S Tsuboyama, A Yokokawa, T Furuta. Tokyo University of Pharmacy and Life Sciences, Department of Medicinal Chemistry and Clinical Pharmacy, Japan

Cytochrome P450 3A (CYP3A) is the most abundant CYP enzyme and is involved in metabolism of 50% of currently prescribed to patients. It is well known that CYP3A activity has large inter-individual variability. The genetic polymorphism of CYP3A cannot explain the variability in CYP3A-mediated metabolism. Therefore, phenotyping of CYP3A is just as important for personalized medicine as therapeutic drug monitoring. We have previously reported evidence for the validity of endogenous cortisol 6β-hydroxylation clearance as a new index for in vivo CYP3A phenotyping in humans and reported inter-individual variability of CYP3A activity was 4-fold and intra-individual variability, diurnal and day-to-day variabilities were 1.1 to 3.4 fold. Some evidence suggests that the CYP3A activity of women is higher than that of men. The female sex steroids estrogen and progesterone was thought to play a role in modulation of this sex-related difference. During menstrual cycle, the concentration of endogenous steroid changes significantly. This study evaluated change in the in vivo activity of CYP3A during the menstrual cycle in healthy women by using endogenous cortisol 6β-hydroxylation clearance as an index. Three young healthy adult women participated in the study of day-to-day variation of in vivo CYP3A activity during the menstrual cycle. Blood samples were obtained at 10:00, 11:00, and 12:00 everyday, every second or third day for 39 - 52 days. The 6β-hydroxylation clearance (CLm(6β)) was calculated as the amount of 6β-hydroxycortisol excreted in urine over a 2-hour period divided by the corresponding 2-hour AUC of cortisol in plasma. Plasma concentrations of endogenous cortisol and urinary excreted amounts of 6β-hydroxycortisol were analyzed by GC/MS and HPLC. The serum concentration of estradiol rised from 10~40 pg/ml in the early follicular phase to 50~271 pg/ml in the periovulatory phase and decreased to 20~162 pg/ml in the luteal phase. The concentration of progesterone in the follicular phase was below 0.3 ng/ml and increased to 10~17 ng/ml in the luteal phase. The mean values for CLm(6β) in each subject for 29 - 52 days were 3.28, 2.49, and 1.76 ml/min respectively and an approximately 1.9-fold interindividual variability of CYP3A activity (mean) was observed. Day-to-day intraindividual variability of the 6β-hydroxylation clearance (CLm(6β)) was 2.43 ~ 3.14-fold (mean: 2.82-fold). The highest value was 5.68 ml/min for Subject 1 and the lowest was 0.91 ml/min for Subject 2. A major peak in the CYP3A activity was observed in the early-follicular or late-follicular phases during the menstrual cycle in three female subjects. Another major peak was also detected in the mid-luteal phase. Although detailed mechanism underlying a change in CYP3A activity during the menstrual cycle is unclear, the peak of the CLm(6β) appeared after 7 to 15 days of the peak concentration of estradiol. It is important CYP3A-phenotyping or evaluating in vivo CYP3A activity to prediction of optimal dosage range to improve the therapeutic outcome and to minimize adverse effects during the menstrual cycle.

Reference:

Furuta T et al. Drug Metab Dispos, 2003; 31: 1283-1287.