CYP2C19基因多态性对奥美拉唑药动学与相对生物利用度的影响  

Effects of CYP2C19 polymorphism on pharmacokinetic profile and comparative bioavailability of omeprazole

作　　者：马晶晶[1] 李金恒[1] 曹晓梅[1] 张尊建[2] 田媛[2] 

机构地区：[1]南京大学医学院临床学院,南京军区南京总医院药理科,江苏南京210002 [2]中国药科大学分析测试中心,江苏南京210009

出　　处：《中国药理学通报》2010年第2期258-262,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No30472055)

摘　　要：目的在中国男性健康受试者中研究CYP2C19基因多态性对奥美拉唑药代动力学及不同奥美拉唑制剂相对生物利用度的影响。方法筛选18名男性健康志愿者,其中CYP2C19野生型(w/w)、CYP2C19突变杂合子(w/m)、CYP2C19突变纯合子(m/m)各6名。采取随机双交叉试验,受试者随机口服试验制剂或参比制剂奥美拉唑肠溶胶囊40mg。抽取血样3ml至给药后12h。1wk后交叉服药。采用LC/MS法测定血浆奥美拉唑浓度,用3P97软件进行个体药动学建模并估算药动学参数。结果w/w、w/m、m/m组参比制剂奥美拉唑的AUC与Cmax分别为1178.44±340.24、2328.10±1011.83、5062.02±1097.29μg.h.L-1与602.87±118.25,926.43±134.48,1406.29±233.58μg.L-1,3组间差异存在显著性(P<0.05)。ke、CL/F、T21和Vd/F也均存在组间差异(P<0.05)。w/w、w/m、m/m组试验制剂奥美拉唑的AUC与C/max分别为1224.82±531.67、2723.34±519.29、5692.49±1575.35μg.h.L-1与618.74±231.43、910.67±125.99、1303.31±152.01μg·L-1,3组间差异存在显著性(P<0.05)。3组间的ke、CL/F、T21和Vd/F等参数差异均有显著性(P<0.05)。w/w、w/m、m/m组奥美拉唑的相对生物利用度分别为94.29%±14.06%、93.08%±11.22%、91.84%±13.03%,3组间差异无统计学意义(P>0.05)。结论不同的CYP2C19基因型,表现为不同的CYP2C19酶活性,影响奥美拉唑的血药浓度和体内药动学过程。临床患者在使用奥美拉唑治疗前进行CYP2C19基因分型,将有利于优化个体治疗方案。CYP2C19基因多态性对奥美拉唑的相对生物利用度无影响。Aim To investigate the effects of CYP2C19 polymorphism on the pharmacokinetics and comparative bioavailability of omeprazole in Chinese population. Methods Eighteen healthy male volunteers were selected,of whom 6 were CYP2C19 wild type （w/w） ,6 were CYP2C19 heterozygous variant （w/m） and the rest were CYP2C19 homozygous variant（m/m）. A randomized two-period crossover study was performed. Subjects were assigned to receive test or reference omeprazole as a single oral dose of 40 mg randomly. After a washout period of one week, subjects received the alternative omeprazole formulation. Multiple blood samples of 3 ml were obtained over 12 h after dosing and plasma concentrations of omeprazole were measured by LC/ MS method. The modeling of individual pharmacokinetics and the pharmacokinetic parameters of omeprazole were estimated by 3P97. Results The AUC and Cmax of reference omeprazole formulation in w/w, w/m, m/m groups were 1178.44 ± 340.24,2328.10 ±1011.83, 5062. 02 ± 1097.29 μg · h · L^-1 and 602. 87 ± 118.25,926. 43 ± 134.48, 1406.29 ± 233.58 μg · L^-l, respectively, with significant differences among the three groups （ P 〈 0.05 ）. Significant differences were also observed in other pharmacokinetic parameters suchas kc,CL/F,t1/2 and Vd/F among the three groups（P 〈 0. 05 ）. With regard to test omeprazole formulation, the AUC and Cmax in W/W, w/m, m/m groups were 1224.82 ± 531.67, 2723.34 ± 519.29,5692, 49 ±1575.35 μg · h · L^-1 and 618.74 ±231.43,910. 67 ±125.99,1303.31 ± 152. 01 μg · L^-1 , respectively, which ,as well as kc CL/F t1/2 and Vd/F were significant different among the three groups （ P 〈 0. 05 ）. No significant differences were observed in comparative bioavailability among groups with the values of 94.29% ±14.06% ,93.08% ± 11.22% ,91.84% ± 13.03% in w/w, w/m, m/m groups respectively （P 〉 0. 05）. Conclusions Different CYP2C19 genotypes, leading to functional heterogeneity of CYP2C19, may affect pharmaeokinetie profile of omeprazole. Therefor

关 键 词：奥美拉唑 CYP2C19 基因多态性 药动学 相对生物利用度 中国人群 

分 类 号：R345.99[医药卫生—基础医学] R394-3