Sugawara Michiko, Condon Krista, Liang Earvin, DesJardins Christopher, Schuck Edgar, Kusano Kazutomi, Lai W George
Medical Communication Section, Medical Division, Eisai Co., Ltd., Nishigoken-cho 13-1, Shinjuku-ku, Tokyo, 162-0812, Japan.
DMPK-Andover, Biopharmaceutical Assessments, Eisai Inc., Ltd., Massachusetts, USA.
Cancer Chemother Pharmacol. 2017 Aug;80(2):377-384. doi: 10.1007/s00280-017-3369-7. Epub 2017 Jun 29.
Eribulin, a synthetic analog of the natural product halichondrin B, is a microtubule dynamics inhibitor. In this study, we report the pharmacokinetic profiles of eribulin in mice, rats, and dogs following intravenous administrations with optimized and validated bio-analytical methods.
Eribulin was administered at 0.5 and 2 mg/kg in mice, 0.5 and 1 mg/kg in rats, and 0.08 mg/kg in dogs. Tumor and brain penetration of eribulin was also evaluated in LOX human melanoma xenograft models. Concentrations in plasma, tumor, and brain were measured by the LC-MS/MS method.
The profiles of eribulin were characterized by extensive distribution, moderate clearance, and slow elimination in the three species. The pharmacokinetics are linear in mice and rats. In xenograft mice, the penetration into the brain was low, as expected, since eribulin is a P-glycoprotein substrate. In contrast to disposition in brain, the exposure of eribulin was approximately 20-30 times higher in tumor than that in plasma and half-lives were 17.8-35.9 h after both single and multiple dose regimens.
Eribulin was distributed rapidly and eliminated slowly in mice, rats, and dogs. The exposure of eribulin was approximately 20-30 times higher in tumor than in plasma in xenograft mice. These results might be caused by eribulin's mechanism of action including increased perfusion in tumor by vascular remodeling effect.
艾日布林是天然产物海兔毒素B的合成类似物，是一种微管动力学抑制剂。在本研究中，我们采用优化和验证的生物分析方法，报告了艾日布林在小鼠、大鼠和犬静脉给药后的药代动力学特征。
艾日布林的给药剂量分别为小鼠0.5和2mg/kg、大鼠0.5和1mg/kg、犬0.08mg/kg。还在人LOX黑色素瘤异种移植模型中评估了艾日布林的肿瘤和脑渗透情况。采用液相色谱-串联质谱法测定血浆、肿瘤和脑组织中的浓度。
艾日布林在这三种物种中的特征为分布广泛、清除率中等和消除缓慢。在小鼠和大鼠中，药代动力学呈线性。在异种移植小鼠中，正如预期的那样，由于艾日布林是P-糖蛋白底物，其脑渗透较低。与在脑中的分布情况相反，在单次和多次给药方案后，艾日布林在肿瘤中的暴露量比血浆中高约20-30倍，半衰期为17.8-35.9小时。
艾日布林在小鼠、大鼠和犬中分布迅速且消除缓慢。在异种移植小鼠中，艾日布林在肿瘤中的暴露量比血浆中高约20-30倍。这些结果可能是由艾日布林的作用机制引起的，包括通过血管重塑效应增加肿瘤灌注。
