title: Interactions between the chemotherapeutic agent eribulin mesylate (E7389) and P-glycoprotein in CF-1 abcb1a-deficient mice and Caco-2 cells.
abstract: 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.
authors.affiliation: DMPK-Andover, Biopharmaceutical Assessments, Eisai Inc., Andover, MA, USA. jesse_taur@eisai.com
authors.forename: Jan-Shiang
authors.initials: JS
authors.lastname: Taur
authors.forename: Christopher S
authors.initials: CS
authors.lastname: DesJardins
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Schuck
authors.forename: Y Nancy
authors.initials: YN
authors.lastname: Wong
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D004347:Drug Interactions; D005663:Furans / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007659:Ketones / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008698:Mesylates / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D000095662:Polyether Polyketides
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; D008698:Mesylates; C507084:Abcb1b protein, mouse; C490954:eribulin; D000095662:Polyether Polyketides