质子泵抑制剂对大鼠体内氯吡格雷抗血小板作用和代谢的影响

Effects of Proton Pump Inhibitors on the Antiplatelet Activity and Metabolism of Clopidogrel in Rats

关键词:  质子泵抑制剂  大鼠  氯吡格雷  抗血小板  代谢

Key words:  proton pump inhibitors  rat  clopidogrel  antiplatelet  metabolism

摘要:

目的 研究各种质子泵抑制剂（proton pump inhibitors，PPIs）对大鼠体内氯吡格雷抗血小板作用和代谢的影响。方法 将40只SD ♂大鼠随机分为氯吡格雷组、氯吡格雷+雷贝拉唑组、氯吡格雷+泮托拉唑组、氯吡格雷+兰索拉唑组和氯吡格雷+奥美拉唑组，每组8只。氯吡格雷、雷贝拉唑、泮托拉唑、兰索拉唑和奥美拉唑的给药剂量分别为6.25，1.8，3.6，2.7，3.6 mg·kg^-1·d^-1，连续给药7 d。分别使用光学比浊法和血管扩张刺激磷酸蛋白检测法检测最大血小板聚集率（maximum platelet aggregation rate，MPA）和血小板反应指数（platelet response index，PRI），并通过LC-MS/MS检测氯吡格雷及其活性代谢物H4的血药浓度。结果 氯吡格雷+雷贝拉唑组、氯吡格雷+兰索拉唑组和氯吡格雷+奥美拉唑组的MPA和PRI均显著高于氯吡格雷组，氯吡格雷+泮托拉唑组的MPA和PRI显著低于氯吡格雷+奥美拉唑组（P<0.05）。与氯吡格雷组比较，氯吡格雷+雷贝拉唑组、氯吡格雷+兰索拉唑组和氯吡格雷+奥美拉唑组的氯吡格雷血药浓度升高，H4血药浓度降低，但差异无统计学意义。结论 联用雷贝拉唑、兰索拉唑及奥美拉唑均会减弱氯吡格雷的抗血小板作用，其中泮托拉唑的抑制作用最弱，奥美拉唑的抑制作用最强。

Abstract:

OBJECTIVE To study the effects of different proton pump inhibitors(PPIs) on the antiplatelet activity and metabolism of clopidogrel in rats. METHODS Forty SD male rats were randomly divided into clopidogrel group, clopidogrel +rabeprazole group, clopidogrel+pantoprazole group, clopidogrel+lansoprazole group, and clopidogrel+omeprazole group, with 8 rats in each group. The doses of clopidogrel, rabeprazole, pantoprazole, lansoprazole, and omeprazole were 6.25, 1.8, 3.6, 2.7, 3.6 mg·kg·d^-1, respectively. Continuous administration for 7 d. The maximum platelet aggregation rate(MPA) and platelet response index(PRI) were detected by optical heterometry method and vasodilator stimulated phosphoprotein assays, respectively. The plasma concentrations of clopidogrel and its active metabolite H4 in rats were detected by LC-MS/MS. RESULTS The MPA and PRI of clopidogrel+rabeprazole group, clopidogrel+lansoprazole group, and clopidogrel+omeprazole group were significantly higher than those of clopidogrel group(P<0.05). The MPA and PRI of clopidogrel+pantoprazole group were significantly lower than those of clopidogrel+omeprazole group(P<0.05). Compared with clopidogrel group, the plasma concentrations of clopidogrel were increased and the plasma concentrations of H4 were decreased in clopidogrel+rabeprazole group, clopidogrel+lansoprazole group, and clopidogrel+omeprazole group, but the changes were not significant. CONCLUSION Rabeprazole, lansoprazole, and omeprazole attenuated the antiplatelet effect of clopidogrel. Among these PPIs, pantoprazole has the weakest inhibitory effect and omeprazole has the strongest inhibitory effect on antiplatelet effect of clopidogrel.