探讨细胞色素（cytochrome，CYP）2C19基因多态性对老年人联用质子泵抑制剂（proton pump inhibitator，PPI）与氯吡格雷的抑酸和抗血小板效果的影响。

选取2014年3月至2015年1月复旦大学附属华山医院老年病科收治的住院患者100例，均规律服用标准剂量PPI和（或）氯吡格雷。采用生物芯片法检测患者外周血CYP2C19基因型，根据基因型的不同代谢程度分组（强、中、弱代谢型组），测定并比较不同代谢型组及各组内使用不同药物患者的胃液pH值、血小板抑制率（采用血栓弹力图检测）、PAG（M）（采用光学比浊法测定）。采用χ²检验分析CYP2C19基因型是否符合Hardy-Weinberg平衡；多组间比较应用单因素方差分析，进一步多重比较采用t检验；两组间的比较采用t检验。

强、中、弱代谢型组分别为42、46、12例；其中强代谢型组中单用PPI、单用氯吡格雷及PPI+氯吡格雷患者分别为16、14、12例，中代谢型组分别为22、10、14例，弱代谢型组分别为4、4、4例。CYP2C19等位基因的分布符合Hardy-Weinberg遗传平衡（χ²=0.49，P>0.05）。强、中、弱代谢型组间年龄、性别、血常规、肝肾功能、电解质、proBNP、血糖的差异均无统计学意义（均P>0.05）。强、中、弱代谢组中单用PPI患者血小板抑制率分别为（76.3±13.1）%、（55.9±19.1）%、（29.9%±6.1）%，差异有统计学意义（F=14.82，P<0.05）；单用氯吡格雷患者血小板抑制率分别为（76.3±13.1）%、（55.9±19.1）%、（29.9%±6.1）%，PAG（M）分别为（33.2±12.1）%、（35.2±13.8）%、（65.4±8.3）%，差异均有统计学意义（F=14.82、10.02，P<0.05或0.01）；PPI+氯吡格雷联用患者胃液pH值分别为3.66±0.7、4.5±0.5、5.0±0.7，血小板抑制率分别为（67.3±12.7）%、（40.6±25.8）%、（3.9±4.3）%，PAG（M）分别为（36.3±11.3）%、（56.2±24.0）%、（75.5%±12.3）%，差异均有统计学意义（F=9.33、15.46、7.08，P<0.05或0.01）。强代谢型组内，PPI+氯吡格雷与单用PPI患者胃液pH值的差异，以及PPI+氯吡格雷与单用氯吡格雷患者血小板抑制率及PAG（M）的差异均无统计学意义（t=-0.15、-1.70、0.67，均P>0.05）；中代谢型组内，PPI+氯吡格雷组与单用PPI患者胃液pH值的差异及PPI+氯吡格雷与单用氯吡格雷患者血小板抑制率的差异均无统计学意义（t=0.41、-1.05，P>0.05），仅PPI+氯吡格雷与单用氯吡格雷患者PAG（M）的差异均有统计学意义[（56.2±24.0）%；（35.2±13.8）%；t=2.38，P<0.05]。弱代谢型组内，PPI+氯吡格雷与单用PPI患者胃液pH值的差异及PPI+氯吡格雷与单用氯吡格雷患者PAG（M）的差异无统计学意义（t=-0.13、1.18，均P>0.05），仅PPI+氯吡格雷与单用氯吡格雷患者血小板抑制率的差异有统计学意义[（3.9±4.3）%，（29.9±6.1）%；t=-6.06，P<0.05]。应用经CYP450代谢药、CYP450酶抑制剂、不经CYP450酶代谢药患者胃液pH值分别为4.2±0.8、4.9±0.7、3.9±0.9，差异有统计学意义（F=3.12，P<0.05）。

CYP2C19基因多态性对老年人使用PPI的抑酸效果、氯吡格雷的抗血小板活性均有影响，PPI与氯吡格雷联合使用时可能相互减弱疗效，联用肝CYP450酶抑制剂会降低PPI的疗效。

To study on the effect of CYP2C19 gene polymorphism on the efficacy of PPI or clopidogrel, and analyze the drug-drug interaction of coadministration of PPI and other drugs in the elderly.

The samples of 100 elderly patients, ranged from 75 to 97 years old, who were hospitalized in Department of Geriatrics Huashan hospital Fudan University from March 2014 to January 2015 were included. All patients took standard dose of PPI qd and/or clopidogrel 75 mg qd regularly. CYP2C19 genotype was indentified by microarray method. pH of their succus gastricus was measured, platelet inhibition rate of clopidogrel was determined by thromboelastogram (TEG), and maximum platelet aggregation rate was determined by light transmittance aggregometry (LTA). Kai-square test was applied to analyze the Hardy-Weinberg balance of CYP2C19 genes among patients. ANOVA test was utilized to compare among multiple groups, andt-test was further used to dertermined differences between two groups.

Extensive, intermediate, and poor metabolism groups were 42, 46, and 12 samples respectively. PPI only, clopidogrel only, and PPI+clopidogrel were 16, 14, and 12 samples respectively in extensive metabolism group; 22, 10, and 14 in intermediate metabolism group; 4, 4, and 4 in poor metabolism group. Distribution of CYP2C19 alleles was accorded with Hardy-Weinberg balance (χ²=0.49,P>0.05). No differences of age, gender, blood cells count, hepatic and renal functions, proBNP, and blood glucose among groups (P>0.05). There were difference of platelet inhibition rate in patients taken PPI only in different metabolism groups were (76.3±13.1)%, (55.9±19.1)%, and (29.9%±6.1)%,(F=14.82,P<0.05). In patients taken clopidogrel only, platelet inhibition rate were (76.3±13.1)%, (55.9±19.1)%, and (29.9%±6.1)%, and PAG(M) were (33.2±12.1)%, (35.2±13.8)%, and (65.4±8.3)%. Both of them have significant differences (F=14.82, 10.02,P<0.05 or 0.01). Gastric pH values in PPI+clopidogrel groups were 3.66±0.7, 4.5±0.5, and 5.0±0.7 respectively. Platelet inhibition rate were (67.3±12.7)%, (40.6±25.8)%, and (3.9±4.3)%. PAG(M) were (36.3±11.3)%, (56.2±24.0)%, and (75.5%±12.3)%. All these data have significant differences (F=9.33, 15.46, 7.08,P<0.05 or 0.01). No difference of gastic pH values between PPI+clopidogrel and PPI only in extensive metabolism group; and no difference of platelet inhibition rate and PAG(M) between in PPI+clopidogrel and clopidogrel only patients in extensive metabolism group (t=-0.15,-1.70, 0.67,P>0.05). In intermediate metabolism group, no differences of gastic pH between PPI+clopidogrel and PPI only groups (t=0.41,P > 0.05), and no difference of platelet inhibition rate in PPI+clopidogrel and clopidogrel groups (t=-1.05,P > 0.05), but only PAG(M) of PPI+clopidogrel and clopidogrel groups have significant diffrence [(56.2±24.0)%, (35.2±13.8)%,t=2.38,P<0.05]. In poor metabolism group, no difference of gastric pH values between PPI+clopidogrel and PPI only groups; and no difference of PAG(M) between PPI+clopidogrel and clopidogrel only groups (t=-0.13, 1.18,P>0.05), but only PPI+clopidogrel and clopidogrel groups have difference of platelet inhibition rate [(3.9±4.3)%, (29.9±6.1)%,t=-6.06,P<0.05]. Gastric pH values in patients using CYP450 metabolic mediations, CYP450 inhibitors, and non-CYP450 metabolic mediations were 4.2±0.8, 4.9±0.7, and 3.9±0.9 (F=3.12, P<0.05).

In the elderly, the polymorphism of CYP2C19 gene impacts on both the acid inhibition of PPI and anti-platelet activity of clopidogrel. Coadministration of PPI and clopidogrel may affect their effects. CYP450 inhibitors affect the gastric acid inhibition of PPI when they were coadministrated.