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  本文選題：重度腎功能不全 + 藥代動力學�。� 參考：《中南大學》2014年碩士論文

【摘要】：一、目的 1、建立測定人血漿中艾瑞昔布M0及其羥基代謝產(chǎn)物M1和羧基代謝產(chǎn)物M2濃度的HPLC-MS/MS方法； 2、評價艾瑞昔布及其代謝產(chǎn)物在重度腎功能不全和腎功能正常受試者體內(nèi)的藥代動力學特征,為腎功能不全患者臨床用藥提供參考。 二、方法 1、方法學的建立：此HPLC-MS/MS方法采用液相萃取進行樣品前處理,以地西泮為內(nèi)標(IS)。色譜條件：分析柱為EcLipse XDB-C18(1502.1mm,3.0μm),流動相為含0.1%甲酸的水溶液與含0.1%甲酸的甲醇溶液以體積比3：7混合,流速為0.3mL·min-1。質(zhì)譜條件：電噴霧離子源,正離子MRM掃描分析,M0、M1、M2和IS的離子通道分別為390.2→236.1、386.1→236.1、400.1→236.1和368.4→294.0amu。 2、藥動學研究：采用平行、開放,單周期配對設計,先入組重度腎功能不全患者12例,根據(jù)腎功能不全組的年齡(±5歲)、性別、體重(±15%)進行匹配再入組12例健康志愿者。餐后,口服艾瑞昔布片100mg,于不同時間點采集血樣。采用經(jīng)驗證后的LC-MS/MS法測定艾瑞昔布M0及其主要代謝產(chǎn)物M1和M2的濃度。用WinNonlin軟件計算M0,M1和M2的藥動參數(shù)。使用t檢驗和Wilcoxon秩和檢驗對兩組間的非房室參數(shù)差異進行方差分析。將腎功能指標Ccr與M0,M1和M2主要藥動學參數(shù)進行相關(guān)性分析。 三、結(jié)果 1、方法學考察結(jié)果：本研究建立的HPLC-MS/MS方法中M0、M1、M2和IS的典型色譜保留時間分別為2.36min,1.49min,1.53min和3.62min。該方法經(jīng)準確度、精密度、提取率、特異性實驗等驗證后符合各項方法學考察要求。血漿中M0、M1和M2的濃度分別在0.1～100、0.2～200和2～2000ng.mL-1范圍內(nèi)線性良好,LLOQ分別為0.1、0.2和2ng·mL-1。 2、藥動學結(jié)果：(1)在腎功能不全受試者中,M0、M1和M2的主要藥動學參數(shù)Cmax分別為(22.63±16.89)、(71.69±16.79)、(1671.66±576.41) ng·h·mL-1; Tmax分別為(3.50±1.45)、(3.50+1.45)(4.00±1.65)h；t1/2分別為(11.89±7.79)、(25.95±23.68)、(13.41±8.11)h；AUC(0→t)分別為(183.38±125.50)、(647.46±213.74)、(18465.38±8602.21)ng·h·mL-1; AUC(0→∞)分別為(195.33±135.41)、(665.27±220.48)(18581.15±8579.05)ng·h·mL-1; CL/F分別為(1056.38±1180.75)、(169.24±69.68)、(6.62±3.47)L·h-1；V/F分別為(15850.91±18444.30)、(5586.51±4548.44)、(135.36±110.86)L；MRT(0-t)分別為(10.14±2.71)、(18.12±7.63)、(13.31±4.78)h。(2)在健康受試者中,M0、M1和M2的主要藥動學參數(shù)Cmax分別為(59.94±50.55)、(71.96±15.07)(585.18±190.01) ng·h·mL-1; Tmax分別為(2.63±1.07)、(2.75±0.87)、(2.67±0.78)h；t1/2分別為(8.02±2.97)、(8.16±4.76)、(8.00±3.66)h；AUC(o→t)分別為(477.01±395.73)、(518.58±145.16)、(3855.25±995.14)ng·h·mL-1；AUC(0→∞）分別為(479.39±395.62)、(523.37±144.75)、(3930.04±1018.54)ng·h·mL-1; CL/F分別為(1056.38±1180.75)、(169.24±69.68)、(6.62±3.47)L·h-1；V/F分別為(463.67±463.06)、(205.57±59.68)、(306.58±138.86)L；MRT(o→t)分別為(9.31+2.75)、(8.46±2.12)、(8.83±2.76)h。與健康受試者相比,腎功能不全患者中M0的AUC和Cmax顯著降低(P0.05)；M1的AUC和Cmax升高,但差異不顯著(P0.05),t1/2Tmax、MRT(0-t)V/F顯著增大和延長(P0.05)；M2的Tmax、MRT(0-t)、AUC、Cmax均顯著升高(P0.05),CL/F顯著降低(P0.05)。相關(guān)性分析結(jié)果顯示M2的Ccr與CL/F呈高度相關(guān)性(r=0.8665,P0.05)。 四、結(jié)論 1、本研究中建立的測定人血漿中M0、M1和M2濃度的HPLC-MS/MS方法具有良好的準確度、精密度、靈敏度和特異性,并成功的應用于本課題中受試者體內(nèi)的M0、M1和M2血藥濃度的測定； 2、重度腎功能不全使艾瑞昔布兩個活性代謝產(chǎn)物M1和M2的血漿暴露量增加,使M1和M2的消除減緩,半衰期延長,建議減小艾瑞昔布在重度腎功能不全患者的臨床給藥劑量。
[Abstract]:First, the purpose
1, establish a HPLC-MS/MS method for determining the concentration of M0 and its hydroxyl metabolites M1 and carboxyl metabolites M2 in human plasma.
2, to evaluate the pharmacokinetic characteristics of alisoxib and its metabolites in patients with severe renal insufficiency and normal renal function, and provide a reference for clinical medication in patients with renal insufficiency.
Two, method
1, the establishment of methodology: this HPLC-MS/MS method uses liquid phase extraction for sample pretreatment with diazepam as internal standard (IS). Chromatographic conditions: the column is EcLipse XDB-C18 (1502.1mm, 3 u m), the liquid phase is 0.1% formic acid and methanol solution containing 0.1% formic acid is mixed with 3:7 in volume, and the flow rate is 0.3mL. Min-1. mass spectrometry condition: The ion channels of M0, M1, M2 and IS were 390.2 to 236.1386.1, 236.1400.1 to 236.1 and 368.4 to 294.0amu., respectively, by electrospray ion source and positive ion MRM scanning analysis.
2, pharmacokinetic study: using parallel, open and single cycle matching design, 12 patients with severe renal insufficiency were first enrolled in the group of 12 healthy volunteers according to the age of renal insufficiency (+ 5 years), sex and weight (+ 15%). After meal, the oral Imrecoxib Tablets 100mg was taken at different time points to collect blood samples. The tested LC-MS was adopted. /MS method was used to determine the concentration of alisoxib M0 and its main metabolites, M1 and M2. The pharmacokinetic parameters of M0, M1 and M2 were calculated by WinNonlin software. The variance analysis of the difference of non atrioventricular parameters between the two groups was analyzed using t test and Wilcoxon rank sum test.
Three, the result
1, methodological investigation results: the typical chromatographic retention time of M0, M1, M2 and IS in the HPLC-MS/MS method established in this study was 2.36min, 1.49min, 1.53min, and 3.62min., respectively, after verifying accuracy, precision, extraction rate and specificity test. The concentration of M0, M1 and M2 in plasma was 0.1 ~ The linearity is good in the range of 200 and 2 to 2000ng.mL-1, and LLOQ is 0.1,0.2 and 2ng. ML-1. respectively.
2, the pharmacokinetic results: (1) the main pharmacokinetic parameters of M0, M1 and M2 were (22.63 + 16.89), (71.69 + 16.79), (1671.66 + 576.41) ng / h mL-1, respectively (3.50 + 1.45), (3.50+1.45) (4 + 1.65) h, respectively, respectively. 8 + 125.50), (647.46 + 213.74), (18465.38 + 8602.21) ng. H. ML-1; AUC (0 to 135.41), respectively (195.33 + 135.41), (665.27 + 220.48) (18581.15 + 8579.05) ng. H. ML-1, CL/F, respectively. (10.14 + 2.71), (18.12 + 7.63), (13.31 + 4.78) H. (2) in healthy subjects, the main pharmacokinetic parameters of M0, M1 and M2 were (59.94 + 50.55), (71.96 + 15.07) (585.18 + 190.01) ng. H. ML-1, Tmax respectively, h, t1/2, respectively. ) (477.01 + 395.73), (518.58 + 145.16), (3855.25 + 995.14) ng. H. ML-1, AUC (0 to 395.62) (479.39 + 395.62), (523.37 + 144.75), (3930.04 + 1018.54) ng. H. ML-1, CL/F, respectively. O - t), respectively (9.31+2.75), (8.46 + 2.12), (8.83 + 2.76) H. compared with healthy subjects, the AUC and Cmax of M0 in patients with renal dysfunction significantly decreased (P0.05), M1 AUC and Cmax, but the difference was not significant (P0.05). Decrease (P0.05). Correlation analysis showed that the Ccr of M2 was highly correlated with CL/F (r=0.8665, P0.05).
Four. Conclusion
1, the HPLC-MS/MS method for determining the concentration of M0, M1 and M2 in human plasma has good accuracy, precision, sensitivity and specificity, and has been successfully applied to the determination of M0, M1 and M2 concentration in the subjects of this subject.
2, severe renal insufficiency increases the plasma exposure of the two active metabolites of erioxib M1 and M2, slowing down the elimination of M1 and M2, prolonging the half-life, and recommending reducing the dose of reixib in the patients with severe renal insufficiency.

【學位授予單位】：中南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R96

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本文編號：1848174