雷贝拉唑对大鼠体内氯吡格雷抗血小板聚集作用和代谢的影响研究
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摘要
目的:研究雷贝拉唑(RPZ)对大鼠体内氯吡格雷(CLP)抗血小板聚集作用和代谢的影响。方法:将40只SD大鼠随机分为空白对照组、RPZ组、CLP组、RPZ+CLP组、CLP+RPZ组,每组8只,CLP和RPZ的给药剂量分别为6.75、0.9 mg/kg,两药给药间隔2 h,连续给药14 d。检测各组大鼠血小板聚集率(MPA)、血小板活化指数(PRI)、胃黏膜损伤评分以及血药浓度[氯吡格雷羧酸(CA)及CLP活性巯基代谢物衍生物(AM)],并采用Pearson相关性分析法分析MPA和PRI分别与CA、AM的关系。结果:与空白对照组比较,CLP组、RPZ+CLP组和CLP+RPZ组大鼠的MPA、PRI均明显降低(P<0.05),胃黏膜损伤评分均明显增加(P<0.05),而RPZ组大鼠的MPA、PRI和胃黏膜损伤评分均无明显变化(P>0.05)。与CLP组比较,RPZ+CLP组和CLP+RPZ组大鼠的MPA、PRI均明显升高(P<0.05),胃黏膜损伤评分均明显减小(P<0.05),AM血药浓度明显降低(P<0.05),而3组大鼠的CA血药浓度无明显变化(P>0.05)。MPA和PRI均与AM呈负相关性(r=-0.689、-0.765,P<0.05),而与CA均未见明显的相关性(r=-0.117、0.048,P>0.05)。结论:RPZ对CLP的抗血小板作用、致胃黏膜损伤有一定的抑制作用,两药的给药顺序不影响CLP的代谢。
OBJECTIVE:To study the effects of rabeprazole(RPZ) on in vivo anti-platelet aggregation and metabolism of clopidogrel in rats. METHODS:Totally 40 SD rats were randomly divided into blank control group,RPZ group,CLP group,RPZ + CLP group and CLP + RPZ group,with 8 rats in each group. The dose of CLP and RPZ were 6.75 and 0.9 mg/kg,with medication interval of 2 h,for consecutive 14 d. The maximal platelet aggregation(MPA),platelet reaction index(PRI),gastric mucosal injury score and blood concentration [carboxylic acid of clopidogrel(CA)and active metabolite of clopidogrel(AM)were detected. The relationship of MPA and PRI with CA and AM were analyzed by Pearson relation analysis. RESULTS:Compared with blank control group,MPA and PRI of rats were decreased significantly in CLP group,RPZ+CLP group and CLP+RPZ group(P<0.05). Gastric mucosal injury score was increased significantly(P<0.05),while MPA,PRI and gastric mucosal injury score had no significant change in RPZ group(P>0.05). Compared with CLP group,MPA and PRI were increased significantly in RPZ+CLP group and CLP + RPZ group(P<0.05);gastric mucosal injury score was decreased significantly(P<0.05) and blood concentration of AM was also decreased significantly(P<0.05). Blood concentration of CA in 3 groups had no significant change(P>0.05). MPA and PRI were both negatively related with AM(r=-0.689,-0.765,P<0.05),while they had no significant correlation with CA(r=-0.117, 0.048, P>0.05). CONCLUSIONS: RPZ can inhibit the antiplatelet effect of CLP and CLP-induced gastric mucosal injury,and medication order of two drugs doesn't influence CLP metabolism.
OBJECTIVE:To study the effects of rabeprazole(RPZ) on in vivo anti-platelet aggregation and metabolism of clopidogrel in rats. METHODS:Totally 40 SD rats were randomly divided into blank control group,RPZ group,CLP group,RPZ + CLP group and CLP + RPZ group,with 8 rats in each group. The dose of CLP and RPZ were 6.75 and 0.9 mg/kg,with medication interval of 2 h,for consecutive 14 d. The maximal platelet aggregation(MPA),platelet reaction index(PRI),gastric mucosal injury score and blood concentration [carboxylic acid of clopidogrel(CA)and active metabolite of clopidogrel(AM)were detected. The relationship of MPA and PRI with CA and AM were analyzed by Pearson relation analysis. RESULTS:Compared with blank control group,MPA and PRI of rats were decreased significantly in CLP group,RPZ+CLP group and CLP+RPZ group(P<0.05). Gastric mucosal injury score was increased significantly(P<0.05),while MPA,PRI and gastric mucosal injury score had no significant change in RPZ group(P>0.05). Compared with CLP group,MPA and PRI were increased significantly in RPZ+CLP group and CLP + RPZ group(P<0.05);gastric mucosal injury score was decreased significantly(P<0.05) and blood concentration of AM was also decreased significantly(P<0.05). Blood concentration of CA in 3 groups had no significant change(P>0.05). MPA and PRI were both negatively related with AM(r=-0.689,-0.765,P<0.05),while they had no significant correlation with CA(r=-0.117, 0.048, P>0.05). CONCLUSIONS: RPZ can inhibit the antiplatelet effect of CLP and CLP-induced gastric mucosal injury,and medication order of two drugs doesn't influence CLP metabolism.
引文
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[12]NICOLAU JC,BHATT DL,ROE MT,et al.Concomitant proton-pump inhibitor use,platelet activity,and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization:insights from the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes trial[J].Am Heart J,2015,170(4):683-694.
[13]KRUIK-KOLL?FFEL WJ,VAN DER PALEN J,VANHERK-SUKEL MPP,et al.Decrease in switches to‘unsafe’proton pump inhibitors after communications about interactions with clopidogrel[J].Clin Drug Investig,2017,37(8):787-794.
[14]YI X,HAN Z,ZHOU Q,et al.Concomitant use of proton-pump inhibitors and clopidogrel increases the risk of adverse outcomes in patients with ischemic stroke carrying reduced-function CYP2C19*2[J].Clin Appl Thromb Hemost,2018,24(1):55-62.
[15]NORDEEN JD,PATEL AV,DARRACOTT RM,et al.Clopidogrel resistance by P2Y12 platelet function testing in patients undergoing neuroendovascular procedures:incidence of ischemic and hemorrhagic complications[J].JVasc Interv Neurol,2013,6(1):26-34.
[2]WEI P,ZHANG YG,LING L,et al.Effects of the shortterm application of pantoprazole combined with aspirin and clopidogrel in the treatment of acute STEMI[J].Exp Ther Med,2016,12(5):2861-2864.
[3]SMALL DS,FARID NA,PAYNE CD,et al.Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel[J].J Clin Pharmacol,2008,48(4):475-484.
[4]CHEN K,ZHANG R,LIU H,et al.Impact of the CYP2C19gene polymorphism on clopidogrel personalized drug regimen and the clinical outcomes[J].Clin Lab,2016,62(9):1773-1780.
[5]张庆翔,刘剑刚,史大卓,等.氯吡格雷的不良反应及其防治研究进展[J].中国药房,2013,24(16):1526-1528.
[6]刘煜,任少琳,黄丽云,等.两种质子泵抑制剂治疗冠心病的临床研究[J].中国药房,2017,28(32):4533-4536.
[7]PRECH M,BARTELA E,JANUS M,et al.Effect of a combination of antiplatelet and antithrombotic pretreatment on myocardial perfusion in patients with an acute ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention[J].Coron Artery Dis,2016,27(7):580-585.
[8]LOZANO I,SANCHEZ-INSA E,DE LEIRAS SR,et al.Acute coronary syndromes,gastrointestinal protection,and recommendations regarding concomitant administration of proton-pump inhibitors(omeprazol/esomeprazole)and clopidogrel[J].Am J Cardiol,2016,117(3):366-368.
[9]LIN L,WANG H,CHEN YF,et al.High maintenance dose of clopidogrel in patients with high on-treatment platelet reactivity after apercutaneous coronary intervention:a meta-analysis[J].Coron Artery Dis,2015,26(5):386-395.
[10]龚磊,孙成铭,杨军.CYP2C19:氯吡格雷代谢的关键酶?[J].心血管病学进展,2017,38(2):222-225.
[11]CHEN WC,LIN KH,HUANG YT,et al.The risk of lower gastrointestinal bleeding in low-dose aspirin users[J].Aliment Pharmacol Ther,2017,45(12):1542-1550.
[12]NICOLAU JC,BHATT DL,ROE MT,et al.Concomitant proton-pump inhibitor use,platelet activity,and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization:insights from the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes trial[J].Am Heart J,2015,170(4):683-694.
[13]KRUIK-KOLL?FFEL WJ,VAN DER PALEN J,VANHERK-SUKEL MPP,et al.Decrease in switches to‘unsafe’proton pump inhibitors after communications about interactions with clopidogrel[J].Clin Drug Investig,2017,37(8):787-794.
[14]YI X,HAN Z,ZHOU Q,et al.Concomitant use of proton-pump inhibitors and clopidogrel increases the risk of adverse outcomes in patients with ischemic stroke carrying reduced-function CYP2C19*2[J].Clin Appl Thromb Hemost,2018,24(1):55-62.
[15]NORDEEN JD,PATEL AV,DARRACOTT RM,et al.Clopidogrel resistance by P2Y12 platelet function testing in patients undergoing neuroendovascular procedures:incidence of ischemic and hemorrhagic complications[J].JVasc Interv Neurol,2013,6(1):26-34.