建立并验证了一种灵敏、选择性的 LC-MS/MS 方法，用于在血浆和脑脊液中测定 BMS-708163（一种γ-分泌酶抑制剂），以去质子化或甲酸盐加合离子作为前体离子。
Development and validation of sensitive and selective LC-MS/MS methods for the determination of BMS-708163, a gamma-secretase inhibitor, in plasma and cerebrospinal fluid using deprotonated or formate adduct ions as precursor ions.
机构信息
Bioanalytical Sciences, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08543, USA.
出版信息
J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Sep 1;878(25):2319-26. doi: 10.1016/j.jchromb.2010.06.041. Epub 2010 Jul 6.
BMS-708163 is a gamma-secretase inhibitor that is being developed for the treatment of Alzheimer's disease. Several LC-MS/MS methods have been developed for the determination of BMS-708163 in both plasma and cerebrospinal fluid in support of dog, rat, mouse and human studies. To support non-clinical studies, an LC-MS/MS method with a lower limit of quantitation (LLOQ) of 5 ng/mL, was developed and validated in dog, rat, and mouse plasma by using the deprotonated ion as the precursor ion. To support clinical studies, an LC-MS/MS method with LLOQ of 0.1 ng/mL, was developed and validated in human plasma by using the formate adduct as the precursor ion. Formic acid (0.01%) in water and acetonitrile was found to be the most favorable mobile phases for both deprotonated and formate adduct ions in negative electrospray ionization mode. A combination of a 3M Empore C18 plate for SPE and a Waters Atlantis dC18 analytical column for separation was used to achieve a highly selective solid phase extraction and chromatographic procedure from plasma without dry down and reconstitution steps. In the development of an assay for BMS-708163 in cerebral spinal fluid (CSF), significant non-specific binding of BMS-708163 was observed and resolved with pre- or post-spike of 0.2% Tween 20 into CSF samples. A dilute-and-shoot LC-MS/MS method with LLOQ of 0.1 ng/mL was developed and validated to assess BMS-708163 exposure in human CSF.
BMS-708163 是一种 γ-分泌酶抑制剂，目前正在开发用于治疗阿尔茨海默病。已经开发了几种 LC-MS/MS 方法，用于支持狗、大鼠、小鼠和人体研究中测定 BMS-708163 在血浆和脑脊液中的浓度。为了支持非临床研究，开发了一种 LLOQ 为 5ng/mL 的 LC-MS/MS 方法，并在狗、大鼠和小鼠血浆中进行了验证，使用去质子化离子作为前体离子。为了支持临床研究，开发了一种 LLOQ 为 0.1ng/mL 的 LC-MS/MS 方法，并在人血浆中进行了验证，使用甲酸加合物作为前体离子。在负离子电喷雾模式下，水和乙腈中的甲酸（0.01%）被发现是去质子化和甲酸加合物离子最有利的流动相。采用 3M Empore C18 板固相萃取和 Waters Atlantis dC18 分析柱分离相结合的方法，从无干燥和复溶步骤的血浆中实现了高度选择性的固相萃取和色谱分离。在开发用于脑脊液（CSF）中 BMS-708163 的测定方法时，观察到 BMS-708163 存在显著的非特异性结合，并通过在 CSF 样品中预加或后加 0.2%吐温 20 解决了这一问题。开发并验证了一种 LLOQ 为 0.1ng/mL 的稀释后进样 LC-MS/MS 方法，用于评估人 CSF 中 BMS-708163 的暴露情况。
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