艾瑞昔布在重度肾功能不全受试者的药代动力学研究

发布时间：2018-05-05 15:10

本文选题：重度肾功能不全 + 药代动力学　；参考：《中南大学》2014年硕士论文

【摘要】：一、目的 1、建立测定人血浆中艾瑞昔布M0及其羟基代谢产物M1和羧基代谢产物M2浓度的HPLC-MS/MS方法； 2、评价艾瑞昔布及其代谢产物在重度肾功能不全和肾功能正常受试者体内的药代动力学特征,为肾功能不全患者临床用药提供参考。二、方法 1、方法学的建立：此HPLC-MS/MS方法采用液相萃取进行样品前处理,以地西泮为内标(IS)。色谱条件：分析柱为EcLipse XDB-C18(1502.1mm,3.0μm),流动相为含0.1%甲酸的水溶液与含0.1%甲酸的甲醇溶液以体积比3：7混合,流速为0.3mL·min-1。质谱条件：电喷雾离子源,正离子MRM扫描分析,M0、M1、M2和IS的离子通道分别为390.2→236.1、386.1→236.1、400.1→236.1和368.4→294.0amu。 2、药动学研究：采用平行、开放,单周期配对设计,先入组重度肾功能不全患者12例,根据肾功能不全组的年龄(±5岁)、性别、体重(±15%)进行匹配再入组12例健康志愿者。餐后,口服艾瑞昔布片100mg,于不同时间点采集血样。采用经验证后的LC-MS/MS法测定艾瑞昔布M0及其主要代谢产物M1和M2的浓度。用WinNonlin软件计算M0,M1和M2的药动参数。使用t检验和Wilcoxon秩和检验对两组间的非房室参数差异进行方差分析。将肾功能指标Ccr与M0,M1和M2主要药动学参数进行相关性分析。三、结果 1、方法学考察结果：本研究建立的HPLC-MS/MS方法中M0、M1、M2和IS的典型色谱保留时间分别为2.36min,1.49min,1.53min和3.62min。该方法经准确度、精密度、提取率、特异性实验等验证后符合各项方法学考察要求。血浆中M0、M1和M2的浓度分别在0.1～100、0.2～200和2～2000ng.mL-1范围内线性良好,LLOQ分别为0.1、0.2和2ng·mL-1。 2、药动学结果：(1)在肾功能不全受试者中,M0、M1和M2的主要药动学参数Cmax分别为(22.63±16.89)、(71.69±16.79)、(1671.66±576.41) ng·h·mL-1; Tmax分别为(3.50±1.45)、(3.50+1.45)(4.00±1.65)h；t1/2分别为(11.89±7.79)、(25.95±23.68)、(13.41±8.11)h；AUC(0→t)分别为(183.38±125.50)、(647.46±213.74)、(18465.38±8602.21)ng·h·mL-1; AUC(0→∞)分别为(195.33±135.41)、(665.27±220.48)(18581.15±8579.05)ng·h·mL-1; CL/F分别为(1056.38±1180.75)、(169.24±69.68)、(6.62±3.47)L·h-1；V/F分别为(15850.91±18444.30)、(5586.51±4548.44)、(135.36±110.86)L；MRT(0-t)分别为(10.14±2.71)、(18.12±7.63)、(13.31±4.78)h。(2)在健康受试者中,M0、M1和M2的主要药动学参数Cmax分别为(59.94±50.55)、(71.96±15.07)(585.18±190.01) ng·h·mL-1; Tmax分别为(2.63±1.07)、(2.75±0.87)、(2.67±0.78)h；t1/2分别为(8.02±2.97)、(8.16±4.76)、(8.00±3.66)h；AUC(o→t)分别为(477.01±395.73)、(518.58±145.16)、(3855.25±995.14)ng·h·mL-1；AUC(0→∞）分别为(479.39±395.62)、(523.37±144.75)、(3930.04±1018.54)ng·h·mL-1; CL/F分别为(1056.38±1180.75)、(169.24±69.68)、(6.62±3.47)L·h-1；V/F分别为(463.67±463.06)、(205.57±59.68)、(306.58±138.86)L；MRT(o→t)分别为(9.31+2.75)、(8.46±2.12)、(8.83±2.76)h。与健康受试者相比,肾功能不全患者中M0的AUC和Cmax显著降低(P0.05)；M1的AUC和Cmax升高,但差异不显著(P0.05),t1/2Tmax、MRT(0-t)V/F显著增大和延长(P0.05)；M2的Tmax、MRT(0-t)、AUC、Cmax均显著升高(P0.05),CL/F显著降低(P0.05)。相关性分析结果显示M2的Ccr与CL/F呈高度相关性(r=0.8665,P0.05)。四、结论 1、本研究中建立的测定人血浆中M0、M1和M2浓度的HPLC-MS/MS方法具有良好的准确度、精密度、灵敏度和特异性,并成功的应用于本课题中受试者体内的M0、M1和M2血药浓度的测定； 2、重度肾功能不全使艾瑞昔布两个活性代谢产物M1和M2的血浆暴露量增加,使M1和M2的消除减缓,半衰期延长,建议减小艾瑞昔布在重度肾功能不全患者的临床给药剂量。
[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.

【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

【参考文献】