中国汉族健康男性细胞色素P450酶2C19遗传多态性对艾司西酞普兰在人体内代谢的影响

Relationship between polymorphism of cytochrome P450 2C19 and pharmacokinetics of escitalopram in Chinese healthy volunteers

目的评价中国汉族健康男性志愿者细胞色素P450(CYP450)2C19遗传多态性对艾司西酞普兰(抗抑郁症和惊恐障碍药)在人体内代谢的影响。方法16名志愿者单次口服艾司西酞普兰后,用PCR-测序法测定其CYP2C19基因的基因型,即野生基因型(*1/*1)含有1个突变基因组(*1/*2或*1/*3)及含有2个突变基因组(*2/*2,*3/*3或*2/*3)。用高效液相色谱-荧光检测法测定其血药浓度。比较艾司西酞普兰在CYP2C19不同基因型代谢的差异。结果随突变基因数目增多,血浆艾司西酞普兰AUC显著升高(P<0.01),CLs显著降低(P<0.01)。CLs、AUC0-t及AUC0-∝的差异在3组间表现出基因剂量效应倾向。结论CYP2C19遗传多态性是影响艾司西酞普兰药物代谢的重要因素。

Objective To evaluate the relationship between cytochrome P450 2C19 genotype and pharmacokinetics of escitalopram in healthy young Chinese male subjects. Methods A single dose of escitalopram was administered to sixteen volunteers. Genotypes of these subjects were determined by PCR - based sequencing. The plasma concentrations of escitalopram were determined by high- performance liquid chromatograph （ HPLC ） with fluorescent - detection. The pharmacokinetic parameters were observed among three groups ： wide type （ genotype is ＊ 1/＊ 1 ） , genotypes with one mutant gene （genotypes are ＊ 1/＊ 2 and ＊ 1/＊ 3） and genotypes with two mutant gene （ genotypes are ~ 2/＊ 2, ＊ 3/＊ 3 and ＊ 2/＊ 3）. Results The area under the plasma concentration versus time curve （AUC） of escitalopram increased with the number of mutant genes（P 〈0.01 ）. The clearance （CLs） of escitalopram decreased with the number of mutant genes（P 〈0.01 ）. The difference about AUC, CLs represented a tendency of effect in the gene dosage between different genotypes. Conclusion The study provided evidence that genetic polymorphism of CYP2C19 had very important contribution to the pharmacokinetics of escitalopram.