期刊
XENOBIOTICA
卷 41, 期 4, 页码 320-326出版社
INFORMA HEALTHCARE
DOI: 10.3109/00498254.2010.542256
关键词
P-glycoprotein; eribulin; CF-1 abcb1a-deficient mice; Caco-2 cells; drug-drug interactions
资金
- Eisai, Inc.
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 mu A mu M. 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 mu A mu M 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.
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