Kim Myong-Jin, Bertino Joseph S, Gaedigk Andrea, Zhang Yanhua, Sellers Edward M, Nafziger Anne N
Clinical Pharmacology Research Center, Department of Medicine, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394, USA.
Clin Pharmacol Ther. 2002 Aug;72(2):192-9. doi: 10.1067/mcp.2002.126174.
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.
The objective of this study was to determine the effects of sex and menstrual cycle phase on CYP2C19 activity by using omeprazole.
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.
Twelve women and 8 men were extensive metabolizers (EMs) with a CYP2C19*1/1 genotype, whereas 4 male subjects were heterozygous (CYP2C191/2). 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 CYP2C191/1 EMs (0.875 for men versus 1.070 for women, P =.140). The median metabolic ratios of all individuals with 2C191/*1 and *1/*2 genotypes were 0.94 and 3.75, respectively.
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.
关于性别对细胞色素P450（CYP）2C19活性影响的文献存在矛盾。口服避孕药中使用的外源性女性甾体激素被认为会显著抑制CYP2C19活性。然而，月经周期中内源性甾体激素浓度变化的影响尚未得到研究。
本研究的目的是通过使用奥美拉唑来确定性别和月经周期阶段对CYP2C19活性的影响。
体重在45至66千克之间的白人受试者单次口服30毫克奥美拉唑。体重在67至90千克之间的受试者服用40毫克剂量。12名女性受试者在月经周期的卵泡中期和黄体中期进行了3个完整周期的表型分析。12名男性受试者每14天进行一次表型分析，共12周。奥美拉唑与5'-羟基奥美拉唑的给药后2小时血浆浓度比用作CYP2C19活性的指标。所有受试者均对CYP2C192和3等位基因进行基因分型。
12名女性和8名男性为具有CYP2C19*1/1基因型的广泛代谢者（EMs），而4名男性受试者为杂合子（CYP2C191/2）。卵泡中期和黄体中期访视期间的中位代谢率分别为0.845和0.930（P = 0.7）。性别对CYP2C191/1 EMs中的CYP2C19活性无影响（男性为0.875，女性为1.070，P = 0.140）。所有具有2C191/1和1/*2基因型个体的中位代谢率分别为0.94和3.75。
在健康的白人CYP2C19*1/*1 EMs中，使用奥美拉唑比值时，CYP2C19活性不存在性别差异。观察到基因剂量效应。此外，月经周期中内源性甾体激素浓度的变化并未影响CYP2C19活性。
