注射用雷替曲塞在结、直肠肿瘤患者体内的药动学

Pharmacokinetics of raltitrexed for injection in patients with colorectal carcinoma

目的:建立人血浆中雷替曲塞浓度的HPLC检测方法,评价注射用雷替曲塞在结、直肠肿瘤患者体内的药动学特征。方法:采用HPLCC18色谱柱(250mm×4.6mm,5μm);流动相为乙腈-磷酸盐缓冲液(19:81,pH2.65);流速1.0mL.min-1;柱温30℃;紫外检测波长348nm。8名肿瘤受试者单剂量静脉滴注雷替曲塞注射液3mg.m-2,用HPLC法测定血浆中雷替曲塞的浓度,并计算药动学参数。结果:该测定方法浓度范围在2.5～2000μg.L-1线性关系良好,得回归方程为Y=280.98X+849.82,r=0.9999(n=3)。最低检测限为2.5μg.L-1,提取回收率为85%～105%,批间差和批内差RSD均<15%。肿瘤受试者静脉滴注雷替曲塞后,药物达峰时间(tmax)均在滴注结束时;药峰浓度(Cmax)为(852.2±286.1)μg.L-1;AUC(0-t)为(721.3±159.4)μg.L-1.h;终末半衰期(t1/2z)为(27.4±38.5)h;血浆清除率(CLz)为(3.6±1.2)L.h.m-2;表观分布容积(Vz)为(99.6±86.4)L.m-2。结论:国产注射用雷替曲塞在结、直肠肿瘤受试者体内,主要药动学参数与国外研究结果相近,没有明显种族差异。

OBJECTIVE To establish HPLC method for raltitrexed in human plasma and to study the pharmacokinetics of rahitrexed for injection in patients with colorectal carcinomaMETHODS HPLC analysis was performed using a Kromasil col- umn （250 mm × 4. 6 mm,5 um）; the mobile phase consisted of acetonitrile-phosphate buffer solution （19：81, pH = 2. 65）, the flow rate was 1.0 mL.min^-1 , the temperature of column was about 30℃ and determined at UV （2 = 348 nm）. Eight tumor patients for single-dose pharmacokinetic study received rahitrexrd of 3 mg/m^2 , the plasma concentrations were determined by HPLC method and DAS 2. 0 was applied to assess the plasma concentration time data. RESULTS The calibration curve is linear in the rang of 2.5 -2 000ug·L^-1 ,y= 280. 98X＋ 849. 82,r= 0. 999 9（n = 3）. The minimal detectable drug concentration was 2. 5 ng·mL^-1, the average recovery rate was 85%- 105%, the inter day and intra-day validation were less than 15%. Tumor patients for single-dose pharmacokinetic study, tmax were 0. 25 h; Cmax were（852. 2 ± 296. 1 ）ug·L^-1 ; AUC（0-t）） were （721.3±159. 4） ug·L^-1· h;t1/2x were （27.4 ± 38. 5）h; CLz were （3.6 ±1. 2）L·h-m^-2 and Vz were （99. 6 ± 86.4）L·m^-2. CONCLUSION The main pharmacokinetic parameters of rahitrexed was kindred with foreign literatures,there was no significant difference between different races.