Taur Jan-Shiang, DesJardins Christopher S, Schuck Edgar L, Wong Y Nancy
DMPK-Andover, Biopharmaceutical Assessments, Eisai Inc., Andover, MA, USA.
Xenobiotica. 2011 Apr;41(4):320-6. doi: 10.3109/00498254.2010.542256. Epub 2010 Dec 17.
Eribulin is a new anticancer agent currently in Phase III clinical trials for the treatment of metastatic breast cancer. In the current studies, we have investigated the effects of P-glycoprotein (P-gp) on the in vivo disposition of eribulin using CF-1 abcb1a-deficient mice, and the influence of eribulin on P-gp-mediated efflux of digoxin in Caco-2 cells. Eribulin was administered intravenously and orally in both CF-1 wild-type and CF-1 abcb1a-deficient mice. P-gp-mediated efflux of digoxin in Caco-2 cell monolayers was measured in the presence of eribulin. The plasma exposure to eribulin was higher in CF-1 abcb1a-deficient mice than that in CF-1 wild-type mice after intravenous (IV) and oral (PO) administrations. The oral bioavailability of eribulin was 62.3% in CF-1 abcb1a-deficient mice compared with 7.6% in wild-type mice. The brain penetration of eribulin in CF-1 abcb1a-deficient mice was 30-fold greater than that in wild-type mice. Eribulin decreased the efflux ratio of digoxin in a concentration-dependent manner, with the result of IC(50) greater than 10 µM. The [I]/IC(50) of eribulin was estimated to be <0.05. P-gp is likely to limit the oral absorption and brain penetration of eribulin in CF-1 wild-type mice. Eribulin inhibited the efflux of digoxin with IC(50) greater than 10 µM in Caco-2 cells. These results suggest that eribulin, given intravenously at the clinically relevant concentrations, may not alter P-gp-mediated disposition of concurrently administered drugs.
艾瑞布林是一种新型抗癌药物，目前正处于治疗转移性乳腺癌的III期临床试验阶段。在当前的研究中，我们使用CF-1 abcb1a基因缺陷小鼠研究了P-糖蛋白（P-gp）对艾瑞布林体内处置的影响，以及艾瑞布林对Caco-2细胞中P-gp介导的地高辛外排的影响。在CF-1野生型和CF-1 abcb1a基因缺陷小鼠中分别静脉注射和口服艾瑞布林。在存在艾瑞布林的情况下，测量Caco-2细胞单层中P-gp介导的地高辛外排。静脉注射（IV）和口服（PO）给药后，CF-1 abcb1a基因缺陷小鼠体内艾瑞布林的血浆暴露量高于CF-1野生型小鼠。CF-1 abcb1a基因缺陷小鼠中艾瑞布林的口服生物利用度为62.3%，而野生型小鼠中为7.6%。CF-1 abcb1a基因缺陷小鼠中艾瑞布林的脑渗透率比野生型小鼠高30倍。艾瑞布林以浓度依赖性方式降低地高辛的外排率，IC50大于10 μM。艾瑞布林的[I]/IC50估计<0.05。P-gp可能会限制CF-1野生型小鼠中艾瑞布林的口服吸收和脑渗透率。在Caco-2细胞中，艾瑞布林以IC50大于10 μM的浓度抑制地高辛的外排。这些结果表明，在临床相关浓度下静脉注射艾瑞布林可能不会改变同时给药药物的P-gp介导的处置。
