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首页> 外文期刊>Journal of mass spectrometry: JMS >Determination of chemically reduced pyrrolobenzodiazepine SJG-136 in human plasma by HPLC-MS/MS: application to an anticancer phase I dose escalation study
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Determination of chemically reduced pyrrolobenzodiazepine SJG-136 in human plasma by HPLC-MS/MS: application to an anticancer phase I dose escalation study

机译：HPLC-MS / MS测定人血浆中的化学还原吡咯唑二氮杂ZeineSJG-136：应用于抗癌阶段I剂量升级研究

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摘要

SJG-136 1,1'-[[(propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-methylidene-1,2,3, 11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]] (NSC 694501), is a bifunctional pyrrolobenzodiazepine (PBD) dimer that forms selective, irreversible, interstrand DNA cross-links via exocyclic N2 atoms of two guanine bases, with a preference for 5'PuGATCPy binding sites. SJG-136 is highly cytotoxic in human tumor cells in vitro and in human tumor xenograft models in vivo at subnanomolar concentrations and is currently in anticancer phase I clinical trials in the United Kingdom and United States. To support correlative pharmacokinetics studies, a highly sensitive HPLC-MS/MS assay was developed and validated for the reliable quantitation of SJG-136 in human plasma, using the structurally similar PBD dimer DSB-120 as an internal standard. Chemical reduction of SJG-136 to its corresponding amine (SJG-136-H-4, [M + H](+) m/z 561) improved HPLC peak resolution and sensitivity by minimizing complications that arose from the reactivity of the labile imine moieties. Plasma samples were processed by protein precipitation and centrifugal membrane dialysis; components were separated by HPLC using an Agilent Rapid Resolution HT 1.8 mm (2.1 mm x 50 mm) analytical column. The total analysis time from injection to injection was 11 min. Electrospray MS/MS detection of SJG-136-H4 was based on the selected reaction monitoring (SRM) transition [M + H]+ m/z 561 -> 301. The analytical response ratio was linearly proportional to the plasma concentration of SJG-136 over the nominal concentration range of 25 pg/ml to 250 ng/ml, with a coefficient of determination of r >= 0.999. The intrarun absolute %RE was <= 19.6, 14.2, and 14.0% at 0.056, 2.83, and 56.3 ng/ml, respectively. The corresponding %RSD was <= 14.9%, 9.01, and 4.59%. The interday %RSD was <= 2.72, 3.46, and 5.20%. The lower and upper limits of quantitation were 0.056 and 56 ng/ml, respectively; recovery of SJG-136 from plasma was >= 62% across the validated concentration range. The sensitivity of the validated assay was sufficient to detect SJG-136 in human subjects for up to 6 h after intravenous administration of 6 mu g/m(2), the starting dose of an NCI-sponsored dose escalation study.
机译：SJG-136 1,1' - [[（丙烷-1,3-二基）二氧化硅]双[（11As）-7-甲氧基-2-甲基-1,2,3,11a-四氢-5h-pyrrolo [2 ，1-C] [1,4]苯并二氮嘧啶-5-一]（NSC 694501），是一种双官能吡咯唑二氧基（PBD）二聚体，其形成选择性，不可逆，Interstrand DNA通过两种鸟嘌呤碱基的N2原子，偏好5'pugatcpy绑定站点。 SJG-136在体外和人肿瘤异种移植模型中具有高细胞毒性，在亚甲醛浓度的体内，目前在英国和美国的抗癌阶段I临床试验。为了支持相关药代动力学研究，使用结构类似的PBD二聚体DSB-120作为内标，开发并验证了高敏感的HPLC-MS / MS测定并验证了人体血浆中SJG-136的可靠定量。 SJG-136的化学还原到其相应的胺（SJG-136-H-4，[M + H]（+）m / Z 561）通过最小化从不稳定亚胺的反应性产生的并发症来改善HPLC峰值分辨率和敏感性部分。通过蛋白质沉淀和离心膜透析处理等离子体样品;使用HPLC使用Agilent快速分辨率HT 1.8mm（2.1mm×50mm）分析柱分离成分。注射注射的总分析时间为11分钟。 SJG-136-H4的电喷雾MS / MS检测基于所选的反应监测（SRM）转变[M + H] + M / Z 561-> 301。分析响应比与SJG的血浆浓度线性成比例 - 136在标称浓度范围内25pg / ml至250ng / ml，测定系数R> = 0.999。 Intrarun绝对％Re分别为0.056,2.83和56.3ng / ml的<= 19.6,14.2和14.0％。相应的％RSD为<= 14.9％，9.01和4.59％。白杨％RSD为<= 2.72,3.46和5.20％。较低的定量限分别和上限分别为0.056和56ng / ml;在验证浓度范围内，从血浆中恢复来自血浆的SJG-136> = 62％。验证的测定的敏感性足以在静脉内施用6μg/ m（2）后，在静脉内施用后，在人类受试者中检测SJG-136，该研究的NCI赞助剂量升级研究的起始剂量。

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