LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501)
LC-MS/MS assay and dog pharmacokinetics of the dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501)
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DOI：
10.1016/j.jchromb.2006.04.031
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发表时间：
2006-08-07
影响因子：
3
通讯作者：
Ames, Matthew M.
中科院分区：
文献类型：
--
作者：
Buhrow, Sarah A.;Reid, Joel M.;Ames, Matthew M.
二聚吡咯并苯并二氮杂卓SJG-136（NSC 694501）具有强效的体外细胞毒性和体内抗肿瘤活性。SJG-136结合在DNA的小沟中，并通过反应性N-10-C-11/N-10-C-II '亚胺/甲醇胺部分产生G-G链间交联。建立了一种灵敏、特异的液相色谱-串联质谱法（LC/MS/MS），用于血浆中SJG-136的定量测定。SJG-136经C8柱固相萃取分离，C18柱等度洗脱，MS/MS检测，电喷雾离子化后监测m/z 557-m/z 476跃迁。血浆标准曲线的线性范围和定量下限分别为2.8-1800 nM和5 nM。SJG-136血浆蛋白结合具有种属依赖性。人、大鼠和小鼠的未结合分数值分别为25%、16.2%和<1%。犬血浆中的蛋白结合可饱和，在22-720 nM浓度范围内，未结合分数从10.8%增加至22.3%。单次静脉给药后，SJG-136的药代动力学最适合二室开放模型，消除半衰期和血浆清除率值分别为97 min和6.1 mL/min/kg。以1.0 μ g/kg剂量连续5天静脉给药后，SJG-136未在血浆中蓄积。(c)2006 Elsevier B. V.保留所有权利。
The dimeric pyrrolobenzodiazepine SJG-136 (NSC 694501) has potent in vitro cytotoxicity and in vivo antitumor activity. SJG-136 binds in the minor groove of DNA and produces G-G interstrand cross-links via reactive N-10-C-11/N-10-C-ll' imine/carbinolamine moieties. We have developed a sensitive, specific liquid chromatography tandem mass spectrometry (LC/MS/MS) method for the quantitative determination of SJG-136 in plasma. SJG-136 was isolated by solid phase extraction through a C8 column, reverse-phase HPLC separation was accomplished on a C18 column with isocratic elution and MS/MS detection, monitoring the m/z 557-m/z 476 transition after electrospray ionization. The linear range and lower limit of quantitation from plasma standard curves were 2.8-1800 nM, and 5 nM, respectively. SJG-136 plasma protein binding was species-dependent. Values of the unbound fraction in human, rat and mouse were 25%, 16.2% and < 1%, respectively. Protein binding was saturable in dog plasma where the unbound fraction increased from 10.8% to 22.3% over a 22-720 nM concentration range. SJG-136 pharmacokinetics after a single intravenous dose were best fit to a two-compartment open model with elimination half-life and plasma clearance values of 97 min and 6.1 mL/min/kg, respectively. SJG-136 did not accumulate in plasma following intravenous administration of 1.0 mu g/kg doses for five consecutive days. (c) 2006 Elsevier B.V. All rights reserved.