鼠类药代动力学和姜黄素类似物，4-哌啶酮，3,5-双[(2-氟苯基)亚甲基]-乙酸酯(3E,5E)(EF-24;NSC 716993)的代谢。
Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5-bis[(2-fluorophenyl)methylene]-acetate(3E,5E) (EF-24; NSC 716993).
机构信息
Department of Oncology, Division of Oncology Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA,
出版信息
Cancer Chemother Pharmacol. 2014 Jun;73(6):1137-46. doi: 10.1007/s00280-014-2447-3. Epub 2014 Apr 24.
PURPOSE
Curcumin, a keto-enol constituent of turmeric, has in vitro and in vivo antitumor activity. However, in vivo potency is low due to poor oral absorption. The mono-carbonyl analog, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone acetate (EF-24, NSC 716993), exhibited broad-spectrum activity in the NCI anticancer cell line screen and potent antiangiogenesis activity in a HUVEC cell migration assay. The purpose of this study was to characterize the preclinical pharmacology of EF-24 in mice.
METHODS
EF-24 plasma stability, protein binding, pharmacokinetics, and metabolism were characterized utilizing an LC/MS/MS assay.
RESULTS
An LC/MS/MS assay incorporated protein precipitation with methanol, reverse-phase HPLC separation under gradient elution using an aqueous methanol mobile phase containing 0.1 % formic acid, and positive electrospray ionization detection of the m/z 312 > 149 transition for EF-24. The assay was linear over the range 7.8-1,000 nM. Plasma protein binding was >98 % with preferential binding to albumin. EF-24 plasma disposition in mice after i.v. administration of a 10 mg/kg dose was best fit to a 3-compartment open model. The terminal elimination half-life and plasma clearance values were 73.6 min and 0.482 L/min/kg, respectively. EF-24 bioavailability was 60 and 35 % after oral and i.p. administration, respectively. NADPH-dependent metabolism of EF-24 loss in liver microsomal preparations yielded several metabolites consistent with EF-24 hydroxylation and reduction.
目的
姜黄素是姜黄中的一种酮烯醇化合物，具有体外和体内抗肿瘤活性。然而，由于口服吸收不良，其体内效力较低。单羰基类似物 3,5-双[(2-氟苯基)亚甲基]-4-哌啶酮乙酸盐（EF-24，NSC 716993）在 NCI 抗癌细胞系筛选中表现出广谱活性，并在 HUVEC 细胞迁移测定中表现出强烈的抗血管生成活性。本研究的目的是表征 EF-24 在小鼠中的临床前药理学特性。
方法
利用 LC/MS/MS 测定法，对 EF-24 的血浆稳定性、蛋白结合、药代动力学和代谢进行了表征。
结果
一种 LC/MS/MS 测定法采用甲醇沉淀蛋白，在反相 HPLC 分离下，采用含 0.1%甲酸的甲醇水流动相进行梯度洗脱，并对 EF-24 的 m/z 312>149 跃迁进行正电喷雾电离检测。该测定法在 7.8-1000 nM 范围内呈线性。血浆蛋白结合率>98%，优先与白蛋白结合。在静脉注射 10mg/kg 剂量后，EF-24 在小鼠体内的血浆处置情况最佳拟合为三房室开放模型。终末消除半衰期和血浆清除率值分别为 73.6 分钟和 0.482 L/min/kg。口服和腹腔内给药后，EF-24 的生物利用度分别为 60%和 35%。EF-24 在肝微粒体制剂中的 NADPH 依赖性代谢导致几种代谢物的损失，这些代谢物与 EF-24 的羟化和还原一致。
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