CYP2C19基因多态性对雷贝拉唑钠药动学影响的研究
发布时间：2018-08-26 15:40
【摘要】：目的：单剂量给予雷贝拉唑钠口腔崩解片或雷贝拉唑钠肠溶片20mg后,考察CYP2C19基因多态性对雷贝拉唑钠药动学的影响。 方法：首先,进行药动学研究需要建立可靠的生物样品检测方法,由于雷贝拉唑钠对酸、光照、温度不稳定,本文充分借鉴了目前已有的HPLC、HPLC-MS. HPLC-MS/MS等测定方法在保持雷贝拉唑钠稳定方面所采取的措施,并在此基础上建立了HPLC法测定雷贝拉唑钠血药浓度的方法；其次,24名受试者随机交叉服用雷贝拉唑钠口腔崩解片和雷贝拉唑钠肠溶片,在规定的时间点采血,使用上述HPLC法检测血药浓度；再次,分别检测受试者CYP2C19*2、CYP2C19*3、CYP2C19*17等位基因突变的情况,以直接测序的方法检测受试者基因型,并据此将其分为不同的表现型组；最后,结合血药浓度数据及基因分型结果分别统计分析不同表现型组间药动学参数的差异。 结果：首先,HPLC方法线性范围为10-2000μg.L-1, r2=0.998,最低定量限为10μg·L-1,低、中、高浓度样品的提取回收率分别为(80.58±7.52)%、(86.96±2.31)%、(92.24±2.41)%,批内相对标准差分别为2.76%～10.92%、2.42%～4.34%、1.91%～2.38%,批间相对标准差分别为9.91%、3.77%、3.20%,准确度分别为(102.85±8.14)%、(99.68±2.41)%、(100.92±±2.07)%；其次,23名受试者完成实验,21名受试者血药浓度数据纳入统计分析,其基因分型及分布结果为CYP2C19*1/*1(homEMs,n=7),CYP2C19*1/*2(hetEMs,n=11),CYP2C19*2/*2(PMs,n=3),未发现CYP2C19*17等位基因；最后,由药动学参数的均值比较结果发现,Tmax在三组间没有差异,口腔崩解片的参数Cmax在三组间没有差异,AUC0-t在任意两组间均有显著性差异,AUC0-∞在homEMs和PMs组间有显著差异,t1/2在homEMs和PMs组、hetEMs和PMs组间有显著差异；肠溶片的参数AUC0-t、AUC0-∞在hetEMs和homEMs组、hetEMs和PMs间有显著差异,Cmax在homEMs和hetEMs组间有显著差异,t1/2在任意两组间有显著差异。 结论：HPLC方法专一、准确、快速,样品取样量少,适用于雷贝拉唑钠人体药代动力学研究；CYP2C19基因多态性对雷贝拉唑钠的AUC、Cmax、t1/2有影响,但是服用不同制剂时,AUC、Cmax、t1/2在三种基因型间的差异表现不一致。
[Abstract]:Aim: to investigate the effect of CYP2C19 gene polymorphism on the pharmacokinetics of Rabeprazole sodium orally disintegrating tablets or rabeprazole enteric-coated tablets (20mg) after a single dose of rabeprazole sodium disintegrating tablets or rabeprazole sodium enteric-coated tablets. Methods: first of all, the pharmacokinetic study needs to establish a reliable method for the detection of biological samples. Because of the instability of acid, light and temperature of rabeprazole sodium, this paper fully draws lessons from the existing HPLC,HPLC-MS.. The measures taken by HPLC-MS/MS et al in maintaining the stability of rabeprazole sodium. On the basis of this, a method for the determination of the blood concentration of rabeprazole sodium by HPLC method was established. Secondly, 24 subjects were randomly cross-administered with Rabeprazole sodium oral disintegrating tablets and rabeprazole sodium enteric tablets. Blood samples were collected at a specified time point, and the blood concentration was detected by the HPLC method mentioned above. Thirdly, the allele mutation of CYP2C19*2,CYP2C19*3,CYP2C19*17 was detected respectively. The genotypes were detected by direct sequencing and divided into different phenotypes. Finally, the differences of pharmacokinetic parameters among different phenotypes were statistically analyzed in combination with blood drug concentration data and genotyping results. 缁撴灉锛氶鍏，
本文编号：2205363
[Abstract]:Aim: to investigate the effect of CYP2C19 gene polymorphism on the pharmacokinetics of Rabeprazole sodium orally disintegrating tablets or rabeprazole enteric-coated tablets (20mg) after a single dose of rabeprazole sodium disintegrating tablets or rabeprazole sodium enteric-coated tablets. Methods: first of all, the pharmacokinetic study needs to establish a reliable method for the detection of biological samples. Because of the instability of acid, light and temperature of rabeprazole sodium, this paper fully draws lessons from the existing HPLC,HPLC-MS.. The measures taken by HPLC-MS/MS et al in maintaining the stability of rabeprazole sodium. On the basis of this, a method for the determination of the blood concentration of rabeprazole sodium by HPLC method was established. Secondly, 24 subjects were randomly cross-administered with Rabeprazole sodium oral disintegrating tablets and rabeprazole sodium enteric tablets. Blood samples were collected at a specified time point, and the blood concentration was detected by the HPLC method mentioned above. Thirdly, the allele mutation of CYP2C19*2,CYP2C19*3,CYP2C19*17 was detected respectively. The genotypes were detected by direct sequencing and divided into different phenotypes. Finally, the differences of pharmacokinetic parameters among different phenotypes were statistically analyzed in combination with blood drug concentration data and genotyping results. 缁撴灉锛氶鍏，
本文编号：2205363
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