Effect of sex and menstrual cycle phase on cytochrome P450 2C19 activity with omeprazole used as a biomarker.
BACKGROUND
Literature addressing the effect of sex on cytochrome P450 (CYP) 2C19 activity is conflicting. The exogenous female sex steroid hormones used in oral contraceptives are believed to significantly inhibit CYP2C19 activity. However, the effect of variations in endogenous sex steroid concentrations throughout the menstrual cycle has not been investigated.


OBJECTIVE
The objective of this study was to determine the effects of sex and menstrual cycle phase on CYP2C19 activity by using omeprazole.


METHODS
White subjects with body weights between 45 and 66 kg received a single oral dose of 30 mg omeprazole. Those with weights of 67 to 90 kg received a dose of 40 mg. Twelve female subjects were phenotyped during the midfollicular and midluteal phases of the menstrual cycle for 3 complete cycles. Twelve male subjects were phenotyped every 14 days for 12 weeks. The 2-hour postdose plasma concentration ratio of omeprazole to 5'-hydroxyomeprazole was used as a measure of CYP2C19 activity. All subjects were genotyped for CYP2C19*2 and *3 alleles.


RESULTS
Twelve women and 8 men were extensive metabolizers (EMs) with a CYP2C19*1/*1 genotype, whereas 4 male subjects were heterozygous (CYP2C19*1/*2). Median metabolic ratios during the midfollicular and midluteal visits were 0.845 and 0.930, respectively (P =.7). Sex had no effect on CYP2C19 activity in CYP2C19*1/*1 EMs (0.875 for men versus 1.070 for women, P =.140). The median metabolic ratios of all individuals with 2C19*1/*1 and *1/*2 genotypes were 0.94 and 3.75, respectively.


CONCLUSIONS
There is no sex difference in CYP2C19 activity in healthy white CYP2C19*1/*1 EMs with the omeprazole ratios. A gene-dose effect was observed. In addition, variations in endogenous sex steroid concentrations throughout the menstrual cycle did not influence CYP2C19 activity.
Kim
Myong-Jin
MJ
Clinical Pharmacology Research Center, Department of Medicine, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394, USA.
Bertino
Joseph S
JS
Gaedigk
Andrea
A
Zhang
Yanhua
Y
Sellers
Edward M
EM
Nafziger
Anne N
AN
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005498:Follicular Phase; D005838:Genotype; D006801:Humans; D008183:Luteal Phase; D008297:Male; D008597:Menstrual Cycle; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009853:Omeprazole / Q000378:metabolism*; D010641:Phenotype; D012016:Reference Values; D012737:Sex Factors; D044465:White People / Q000235:genetics*
D015415:Biomarkers; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole