Laine K, Tybring G, Bertilsson L
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge University Hospital, Sweden.
Clin Pharmacol Ther. 2000 Aug;68(2):151-9. doi: 10.1067/mcp.2000.108949.
Although it is known that the use of oral contraceptives inhibits oxidative drug metabolism, there is little information regarding their effect on CYP2C19 activity. Moreover, earlier reports suggest that there may be differences in CYP2C19 activity between men and women.
We sought to assess the effect of sex and intake of oral contraceptives on CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole.
To determine CYP2C19 activity in white Swedish subjects, 644 subjects previously phenotyped with mephenytoin and 175 subjects phenotyped with omeprazole were investigated. The 8-hour urinary mephenytoin S/R ratio after ingestion of 100 mg mephenytoin and the plasma concentration ratio of omeprazole/hydroxyomeprazole at 3 hours after ingestion of 20 mg omeprazole were used as measures of CYP2C19 activity. Differences in these ratios and in their frequency distributions were then examined among women with and without oral contraceptives and men. In addition, nearly all subjects in the omeprazole group had been genotyped with regard to the CYP2C192 (ml) allele. Subjects homozygous for the CYP2C192 allele were excluded from the study.
The median mephenytoin S/R ratio was 2.5-fold higher in the subgroup of women taking oral contraceptives compared with either women not taking oral contraceptives (P < .001) or men (P < .001). Similarly, the mean omeprazole/hydroxyomeprazole ratio was twice as high in the oral contraceptive group compared with women not taking oral contraceptives (P < .001) or men (P < .001). However, no differences were evident between women not taking oral contraceptives and men in either the mephenytoin group (P = .48) or the omeprazole group (P = .77). The oral contraceptive-induced inhibitory effect on CYP2C19 activity was similar between the CYP2C19*1/*1 and *1/*2 genotypes, and they were independent of age.
Intake of oral contraceptives significantly inhibits CYP2C19 activity, but there is no true sex-related difference in CYP2C19 activity in healthy, white, Swedish subjects.
尽管已知口服避孕药的使用会抑制药物的氧化代谢，但关于其对CYP2C19活性的影响却知之甚少。此外，早期报告表明，男性和女性之间的CYP2C19活性可能存在差异。
我们试图评估性别和口服避孕药的摄入对以美芬妥英和奥美拉唑作为探针药物所测定的CYP2C19活性的影响。
为了确定瑞典白人受试者的CYP2C19活性，对644名先前用美芬妥英进行过表型分析的受试者和175名用奥美拉唑进行过表型分析的受试者进行了研究。摄入100mg美芬妥英后8小时的尿中美芬妥英S/R比值以及摄入20mg奥美拉唑后3小时的血浆中奥美拉唑/羟基奥美拉唑浓度比值被用作CYP2C19活性的指标。然后在服用和未服用口服避孕药的女性以及男性之间检查这些比值及其频率分布的差异。此外，奥美拉唑组中几乎所有受试者都已针对CYP2C192（ml）等位基因进行了基因分型。CYP2C192等位基因纯合的受试者被排除在研究之外。
与未服用口服避孕药的女性（P < 0.001）或男性（P < 0.001）相比，服用口服避孕药的女性亚组中，美芬妥英S/R比值的中位数高2.5倍。同样，口服避孕药组中奥美拉唑/羟基奥美拉唑的平均比值是未服用口服避孕药的女性（P < 0.001）或男性（P < 0.001）的两倍。然而，在美芬妥英组（P = 0.48）或奥美拉唑组（P = 0.77）中，未服用口服避孕药的女性和男性之间均未发现明显差异。口服避孕药对CYP2C19活性的抑制作用在CYP2C19*1/1和1/*2基因型之间相似，且与年龄无关。
口服避孕药的摄入会显著抑制CYP2C19活性，但在健康的瑞典白人受试者中，CYP2C19活性不存在真正的性别相关差异。
