雷贝拉唑对不同CYP2C19基因型健康志愿者体内氯吡格雷及其活性代谢物药动学的影响

目的:探讨雷贝拉唑对不同CYP2C19代谢型健康志愿者体内氯吡格雷及其活性代谢物药动学特征的影响。方法:选择健康志愿者为对象,根据其CYP2C19基因型按随机数字表法挑选快代谢型、中间代谢型和慢代谢型受试者各8例分组,采用单剂量、随机、开放、两周期的交叉试验设计,各组患者在试验周期内分别单次口服硫酸氢氯吡格雷片300 mg或硫酸氢氯吡格雷片300 mg+雷贝拉唑钠肠溶片20 mg,清洗期为7天。采用超高效液相色谱-串联质谱法检测受试者血浆中氯吡格雷及活性代谢产物H4(MP-H4)的质量浓度,通过DAS 2.0软件计算药动学参数并比较。结果:3种代谢型受试者年龄、身高、体质量、肝酶、血肌酐等一般临床资料比较,差异均无统计学意义(P>0.05)。与单用氯吡格雷者比较,联用雷贝拉唑的快代谢型组受试者体内氯吡格雷的达峰浓度(c_max)和药-时曲线下面积(AUC_0-t)分别上升了36%和27%,MP-H4的c_max和AUC0_0-t分别下降了34%和28%(P<0.01);中间代谢型受试者氯吡格雷的c_max和AUC0_0-t分别上升了19%和18%,MP-H4的c_max和AUC0_0-t分别下降了19%和16%(P<0.05或P<0.01);而慢代谢型受试者联用雷贝拉唑后体内氯吡格雷及MP-H4的c_max、AUC0_0-t以及各代谢型受试者体内氯吡格雷及MP-H4的tmax与单用氯吡格雷者比较,差异均无统计学意义(P>0.05)。结论:在CYP2C19快代谢型和中间代谢型受试者中,联用雷贝拉唑可明显增加氯吡格雷的暴露量并降低其活性代谢产物MP-H4的暴露量;而这种联用对CYP2C19慢代谢型受试者体内氯吡格雷及其活性代谢产物的影响并不显著。

Effects of Rabeprazole on the Pharmacokinetics of Clopidogrel and Its Active Metabolite in Healthy Volunteers with Different CYP2C19 Genotypes

OBJECTIVE:To investigate the effects of rabeprazole on the pharmacokinetic characteristics of clopidogrel and its active metabolite in healthy volunteers with different CYP2C19 genotypes.METHODS:Healthy volunteers were selected as subjects,and then randomly divided into extensive metabolizer(EM)group,intermediate metabolizer(IM)group,and poor metabolizer(PM)group with 8 subjects in each group,according to their CYP2C19 genotypes by random number table.In single-dose,randomized,open,two-cycle-crossover design,each group was given Clopidogrel bisulfate tablets 300 mg or Clopidogrel bisulfate tablets 300 mg+Rabeprazole sodium enteric-coated tablets 20 mg.UPLC-MS/MS method was adopted to detect the concentration of clopidogrel and its active metabolite derivative(MP-H4).The pharmacokinetic parameters were calculated and compared by DAS 2.0 software.RESULTS:There was no statistical significance in clinical data as age,height,body weight,liver enzymes and serum creatinine among 3 kinds of metabolism subjects(P>0.05).Compared with subjects receiving clopidogrel alone,c_max and AUC0_0-t of clopidogrel of subjects combined with rabeprazole in EM group were increased by 36%and 27%,while those of MP-H4 were decreased by 34%and 28%(P<0.01);c_max and AUC0_0-t of clopidogrel of subjects combined with rabeprazole in IM group were increased by 19%and 18%,while those of MP-H4 were decreased by 19%and 16%(P<0.05 or P<0.01);there was no statistical significance in c_max and AUC0_0-t of clopidogrel and MP-H4 in PM group after receiving rabeprazole additionally as well as tmax of clopidogrel and MP-H4 in all metablism subjects,compared with clopidogrel alone(P>0.05).CONCLUSIONS:Among CYP2C19 EM and IM subjects,combined use of rabeprazole can significantly increase the exposure of clopidogrel and decrease the exposure of its active metabolite MP-H4,but has no significant impact on clopidogrel and its active metabolite in CYP2C19 PM subjects.