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

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.