title: Selamectin is a potent substrate and inhibitor of human and canine P-glycoprotein.
abstract: The transport of the antiparasitic agents, ivermectin, selamectin and moxidectin was studied in human intestinal epithelial cell monolayers (Caco-2) and canine peripheral blood lymphocytes (PBL). Both models expressed the mdr1-coded 170 kDa ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Fluxes of the P-gp substrate rhodamine-123 (Rh-123) across Caco-2 monolayers showed that ivermectin and selamectin acted as potent P-gp inhibitors with IC50 values of 0.1 microm. In contrast, moxidectin was a weaker P-gp inhibitor with an IC50 of 10 microm. The transport of radiolabelled ivermectin, selamectin and moxidectin through Caco-2 monolayers showed that ivermectin, selamectin and moxidectin were P-gp substrates with secretory/absorptive ratios of 7.5, 4.7 and 2.6 respectively. Secretory transport of [3H]-ivermectin and [3H]-selamectin was blocked by the P-gp inhibitor, verapamil. Ivermectin and selamectin inhibited the efflux of Rh-123 from PBL and the concentration of inhibition was similar to that of verapamil. In contrast, moxidectin did not have a significant effect on Rh-123 efflux from PBL. The data suggest that ivermectin and selamectin are potent P-gp substrates, while moxidectin is a weak one.
authors.affiliation: Faculty of Veterinary Medicine and Conway Institute of Biomolecular and Biomedical Research, University College, Dublin, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Griffin
authors.forename: N
authors.initials: N
authors.lastname: Fletcher
authors.forename: R
authors.initials: R
authors.lastname: Clemence
authors.forename: S
authors.initials: S
authors.lastname: Blanchflower
authors.forename: D J
authors.initials: DJ
authors.lastname: Brayden
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007559:Ivermectin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000008:administration & dosage / Q000494:pharmacology; D012235:Rhodamines / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000977:Antiparasitic Agents; D018942:Macrolides; D012235:Rhodamines; D007559:Ivermectin; C414354:selamectin; C027837:moxidectin