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Xenobiotica
the fate of foreign compounds in biological systems
Volume 41, 2011 - Issue 4
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Animal Pharmacokinetics and Metabolism

Interactions between the chemotherapeutic agent eribulin mesylate (E7389) and P-glycoprotein in CF-1 abcb1a-deficient mice and Caco-2 cells

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Pages 320-326 | Received 26 Aug 2010, Accepted 18 Nov 2010, Published online: 17 Dec 2010
 

Abstract

  1. 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.

  2. 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.

  3. 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 IC50 greater than 10 µM. The [I]/IC50 of eribulin was estimated to be <0.05.

  4. 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 IC50 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.

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