Quantitative determination of omapatrilat and its metabolites in human plasma by HPLC coupled with tandem mass spectrometry  

液相色谱串联质谱法测定人血浆中奥马曲拉及其代谢物(英文)

作　　者：王洪允[1] 胡玉芳[1] 江骥[1] 胡蓓[1] 

机构地区：[1]中国医学科学院北京协和医院临床药理研究中心

出　　处：《Acta Pharmacologica Sinica》2003年第1期76-86,共11页中国药理学报（英文版）

基　　金：Project supported by Bristol-Myers Squibb Pharmaceutical Company.

摘　　要：AIM: To develop a sensitive and specific analytical method for the quantitative determination of omapatrilat (BMS-186716) and its metabolites (BMS-196087, 225308, 198433, and 253653) in human plasma. METHODS: Methyl acrylate (MA) was selected to react with BMS-186716, 196087, and 253653 to protect the free sulfhydryl groups.High pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to detect the analytes.RESULTS: The method was validated over the concentration range of 0.2-250 μg/L for BMS-186716, 0.5-250μg/L for BMS-196087, 1-250 μg/L for BMS-225308, 2-250 μg/L for BMS-198433, and 10-2500 μg/L for BMS-253653. The limit of quantitation was in turn 0.2, 0.5, 1, 2, and 10 μg/L, respectively. The extraction recovery was on average 60.5％, 88.6％, 76.3％, 71.2％, and 26.6％, respectively. Inter-and intra-day precision of quality control samples (QC) was all within±15％ and accuracy was within 85％-115％. The analytes in human plasma were found to be stable after three cycles of freeze-thaw and for at least 6 h at room temperature (25℃). No significant change was found in reconstituted reagent after 24 h at room temperature and results of long-term stability showed all the analytes in human plasma were stable for at least 3 months at -30℃ freezing condition. CONCLUSION: This method is rapid, sensitive and specific for the pharmacokinetics study of omapatrilat and its metabolites.目的:建立液相色谱串联质谱法测定人血浆中奥马曲拉(BMS-186716)及其四种代谢物(BMS-196087,BMS-225308,BMS-198433和BMS-253653)。方法:以甲基丙烯酸酯对奥马曲拉、BMS-196087和BMS-253653结构中的游离巯基进行衍生化处理后,采用液相进行测定。结果:奥马曲拉及其代谢物在下列范围内具有良好的线性关系:BMS-186716,0.2-250μg/L;BMS-196087,0.5-250μg/L;BMS-225308,1-250μg/L;BMS-198433,2-250μg/L;BMS-253653,10-2500μg/L。最低检测浓度分别为0.2μg/L、0.5μg/L、1.0μg/L、2.0μg/L和10μg/L;平均萃取回收率分别为60.5％、88.％、76.3％、71.2％、26.6％;日内精密度和日间精密度(RSD％)均在±15％之内,相对回收率在85％-115％之间;血浆样品可耐受3次冻融,室温下可 稳定放置6小时,萃取后的样品室温下放置24小时没有任何异常变化,长期稳定性实验显示血浆样品在-30℃条件下可冻存3个月。结论:本方法准确、灵敏、快速、选择性好,能用于奥马曲拉及其代谢物的临床药代动力学研究。

关 键 词：OMAPATRILAT BMS-186716 high pressure liquid chromatography mass spectrometry 

分 类 号：R96[医药卫生—药理学]