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Selamectin is a potent substrate and inhibitor of human and canine P‐glycoprotein
Author(s) -
GRIFFIN J.,
FLETCHER N.,
CLEMENCE R.,
BLANCHFLOWER S.,
BRAYDEN D. J.
Publication year - 2005
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/j.1365-2885.2005.00655.x
Subject(s) - moxidectin , p glycoprotein , verapamil , ivermectin , pharmacology , efflux , ic50 , chemistry , bioavailability , in vitro , biology , biochemistry , multiple drug resistance , antibiotics , zoology , organic chemistry , calcium
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 IC 50 values of 0.1 μ m . In contrast, moxidectin was a weaker P‐gp inhibitor with an IC 50 of 10 μ m . 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 [ 3 H]‐ivermectin and [ 3 H]‐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.