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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
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| 篇名： | 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 |
| TITLE： | Effects of Rabeprazole on the Pharmacokinetics of Clopidogrel and Its Active Metabolite in Healthy Volunteers with Different CYP2C19 Genotypes |
| 摘要： | 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300mg或硫酸氢氯吡格雷片300mg+雷贝拉唑钠肠溶片20mg，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DAS2.0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（cmax）和药-时曲线下面积（AUC0－）t分别上升了36％和27％，MP-H4的cmax和AUC0－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cmax和AUC0－t分别上升了19％和18％，MP-H4的cmax和AUC0－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cmax、AUC0－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。 |
| ABSTRACT： | OBJECTIVE：To investigate the effects of rabepr azole 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 ，cmax and AUC 0－t of clopidogrel of subjects combined with rabeprazole in EM group were increased by 36％ and 27％，while those of MP-H 4 were decreased by 34％ and 28％（P＜0.01）；cmax and AUC 0－t of clopidogrel of subjects combined with rabeprazole in IM group were increased by 19％ and 18％，while those of MP-H 4 were decreased by 19％ and 16％ （P＜0.05 or P＜0.01）；there was no statistical significance in cmax and AUC 0－t of clopidogrel and MP-H 4 in PM group after receiving rabeprazole additionally as well as tmax of clopidogrel and MP-H 4 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-H 4，but has no significant impact on clopidogrel and its active metabolite in CYP2C19 PM subjects. |
| 期刊： | 2021年第32卷第05期 |
| 作者： | 叶艮英，何瑞荣，梁淑贞，周国祥，丁少波 |
| AUTHORS： | YE Genying ，HE Ruirong ，LIANG Shuzhen ，ZHOU Guoxiang ，DING Shaobo |
| 关键字： | 氯吡格雷；活性代谢产物；雷贝拉唑；CYP2C19；基因型；药动学；药物相互作用 |
| KEYWORDS： | Clopidogrel；Active motabolite ；Rabeprazole；CYP2C19；Genotype；Pharmacokinetics；Drug interaction |
| 阅读数： | 458 次 |
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