LC-MS/MS测定尿样瑞舒伐他汀浓度及人体药动学研究

 目的建立HPLC-MS/MS法测定尿样中的瑞舒伐他汀浓度,研究其在健康国人体内的药动学特征。方法选择匹伐他汀为内标,尿样经叔丁基甲醚提取,采用GL Nuclosil C₁₈(2mm×50mm,5μm),以甲醇-水-甲酸(70∶30∶1)为流动相,流速0.25mL·min^-1;质谱检测为正离子方式下的MRM扫描。24例健康男性受试者随机等分为3组,分别每日空腹口服瑞舒伐他汀5,10和20mg,连续7d,测定药后不同时间段的尿药浓度。结果瑞舒伐他汀的线性范围为2～500μg·L^-1(r=0.9998),最低检测质量浓度为2μg·L^-1,提取回收率>75%,日内和日间RSD均≤11.4%。受试者服药后的最大排泄速率均出现在药后5h左右,消除半衰期t_1/2为11.2～15.8h,累积排泄率为10%,比白种人高约2倍。结论在本研究剂量范围内,瑞舒伐他汀呈线性动力学特征,中国人与白种人的药动学特征存在明显的种族差异。

Determination of Rosuvastatin in Urine by HPLC-MS/MS Assay and Study on Its Pharmacokinetics in Healthy Subjects

OBJECTIVE To establish a HPLC-MS/MS method for the determination of rosuvastatin in urine and to investigate its pharmacokinetic characteristics in healthy Chinese subjects.METHODS Rosuvastatin and pitavastatin (IS) were extracted from urine with methyl-tert butyl ether and then separated on a GL Nuclosil C₁₈ column,using methanol-water-formic acid (70∶30∶1)as the mobile phase at a flow rate of 0.25 mL·min^-1. The mass spectrometer was operated with positive electrospray ionization,and quantitation was performed using multiple reaction monitoring (MRM) mode. 24 Subjects were administered randomly with 5,10 or 20 mg rosuvastatin oral dose daily for 7 d. The urine concentrations of rosuvastatin were determined by HPLC-MS/MS method. RESULTS The linear range was 2～500 μg·L^-1 (r=0.999 8) with a lower limit of quantitation of 2 μg·L^-1. The intra- and inter-day precision were below 11.4% and the extraction recovery was above 75%. The maximum observed excretion of rosuvastatin appeared at 5 h and the elimination half-life was about 11.2～15.8 h. Approximately 10% of the dose was recovered in urine,which was much higher (2-fold) than that of Caucasian. CONCLUSION Rosuvastatin exhibited linear pharmacokinetic characteristics over the studied dose range. It had been shown that there was remarkable ethnic difference in pharmacokinetic profiles between Chinese and Caucasian.