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

• Published in: Xenobiotica Vol. 41; no. 4; pp. 320 - 326
• Main Authors: Taur, Jan-Shiang, DesJardins, Christopher S., Schuck, Edgar L., Wong, Y. Nancy
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.04.2011; Taylor & Francis
• Subjects: Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Caco-2 Cells; CF-1 abcb1a-deficient mice; Drug Interactions; drug-drug interactions; eribulin; Furans - metabolism; Furans - pharmacokinetics; Humans; Ketones - metabolism; Ketones - pharmacokinetics; Male; Mesylates - metabolism; Mesylates - pharmacokinetics; Mice; P-glycoprotein
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2010.542256

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 IC50 greater than 10 µM. The [I]/IC50 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 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.