Premium
The interaction between moxidectin and MDR transporters in primary cultures of rat hepatocytes
Author(s) -
DUPUY J.,
LESPINE A.,
SUTRA J. F.,
ALVINERIE M.
Publication year - 2006
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.1365-2885.2006.00721.x
Subject(s) - moxidectin , probenecid , abcg2 , transporter , pharmacology , multidrug resistance associated proteins , p glycoprotein , verapamil , intracellular , multiple drug resistance , multidrug resistance associated protein 2 , chemistry , efflux , adme , drug , atp binding cassette transporter , biology , biochemistry , gene , antibiotics , ecology , anthelmintic , organic chemistry , calcium
The interaction of moxidectin (a macrocyclic lactone, ML) with P‐glycoprotein (P‐gp), multidrug resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP) was studied in primary cultures of rat hepatocytes by measuring the intracellular accumulation of [ 14 C]‐moxidectin over 72 h in the presence of specific inhibitors: for P‐gp, verapamil (10 μ M); for MRPs, MK571 (100 μ M), indomethacin (10 μ M) and probenecid (3.8 mM); and for BCRP, fumitremorgin C (5 μ M). The P‐gp and MRP inhibitors increased significantly ( P < 0.01) by 48.7%, 49.8%, 49.9% and 57.2% the area under the time‐intracellular concentration curve (AUC) of moxidectin in rat hepatocytes, while the BCRP inhibitor, fumitremorgin C, had no effect on the AUC compared with the control. In addition, the mRNAs of all the drug transporters studied were detected in rat hepatocytes from 0 to 72 h. Using this cellular model it has been shown that MRP inhibitors increase moxidectin intracellular concentrations to a similar extent as the P‐gp inhibitor. The identification of all the transporters that interact with MLs remains a challenge, which currently concerns several important therapeutic fields.