【摘要】：目的：單劑量給予雷貝拉唑鈉口腔崩解片或雷貝拉唑鈉腸溶片20mg后,考察CYP2C19基因多態(tài)性對雷貝拉唑鈉藥動學的影響。 方法：首先,進行藥動學研究需要建立可靠的生物樣品檢測方法,由于雷貝拉唑鈉對酸、光照、溫度不穩(wěn)定,本文充分借鑒了目前已有的HPLC、HPLC-MS. HPLC-MS/MS等測定方法在保持雷貝拉唑鈉穩(wěn)定方面所采取的措施,并在此基礎上建立了HPLC法測定雷貝拉唑鈉血藥濃度的方法；其次,24名受試者隨機交叉服用雷貝拉唑鈉口腔崩解片和雷貝拉唑鈉腸溶片,在規(guī)定的時間點采血,使用上述HPLC法檢測血藥濃度；再次,分別檢測受試者CYP2C19*2、CYP2C19*3、CYP2C19*17等位基因突變的情況,以直接測序的方法檢測受試者基因型,并據(jù)此將其分為不同的表現(xiàn)型組；最后,結合血藥濃度數(shù)據(jù)及基因分型結果分別統(tǒng)計分析不同表現(xiàn)型組間藥動學參數(shù)的差異。 結果：首先,HPLC方法線性范圍為10-2000μg.L-1, r2=0.998,最低定量限為10μg·L-1,低、中、高濃度樣品的提取回收率分別為(80.58±7.52)%、(86.96±2.31)%、(92.24±2.41)%,批內(nèi)相對標準差分別為2.76%～10.92%、2.42%～4.34%、1.91%～2.38%,批間相對標準差分別為9.91%、3.77%、3.20%,準確度分別為(102.85±8.14)%、(99.68±2.41)%、(100.92±±2.07)%；其次,23名受試者完成實驗,21名受試者血藥濃度數(shù)據(jù)納入統(tǒng)計分析,其基因分型及分布結果為CYP2C19*1/*1(homEMs,n=7),CYP2C19*1/*2(hetEMs,n=11),CYP2C19*2/*2(PMs,n=3),未發(fā)現(xiàn)CYP2C19*17等位基因；最后,由藥動學參數(shù)的均值比較結果發(fā)現(xiàn),Tmax在三組間沒有差異,口腔崩解片的參數(shù)Cmax在三組間沒有差異,AUC0-t在任意兩組間均有顯著性差異,AUC0-∞在homEMs和PMs組間有顯著差異,t1/2在homEMs和PMs組、hetEMs和PMs組間有顯著差異；腸溶片的參數(shù)AUC0-t、AUC0-∞在hetEMs和homEMs組、hetEMs和PMs間有顯著差異,Cmax在homEMs和hetEMs組間有顯著差異,t1/2在任意兩組間有顯著差異。 結論：HPLC方法專一、準確、快速,樣品取樣量少,適用于雷貝拉唑鈉人體藥代動力學研究；CYP2C19基因多態(tài)性對雷貝拉唑鈉的AUC、Cmax、t1/2有影響,但是服用不同制劑時,AUC、Cmax、t1/2在三種基因型間的差異表現(xiàn)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. 緇撴灉錛氶鍏，

本文編號：2205363