The interaction between moxidectin and MDR transporters in primary cultures of rat hepatocytes

Journal of Veterinary Pharmacology and Therapeutics
Jacques DupuyM Alvinerie

Abstract

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 [14C]-moxidectin over 72 h in the presence of specific inhibitors: for P-gp, verapamil (10 microM); for MRPs, MK571 (100 microM), indomethacin (10 microM) and probenecid (3.8 mM); and for BCRP, fumitremorgin C (5 microM). 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.

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Citations

Jun 21, 2007·Veterinary Research Communications·David J Brayden, Joanna Griffin
May 7, 2010·Journal of Veterinary Pharmacology and Therapeutics·R PérezJ Cox
Jun 2, 2010·Chemico-biological Interactions·Jacques DupuyAnne Lespine
Nov 7, 2006·Journal of Veterinary Pharmacology and Therapeutics·J DupuyM Alvinerie
Mar 13, 2014·Journal of Veterinary Pharmacology and Therapeutics·M BallentA Lifschitz
Apr 18, 2008·European Journal of Pharmacology·Jan A Schrickx, Johanna Fink-Gremmels
Dec 1, 2012·International Journal for Parasitology. Drugs and Drug Resistance·Roger PrichardAnne Lespine
Feb 1, 2020·Journal of Biochemical and Molecular Toxicology·Im-Sook SongHye-Suk Lee
Nov 10, 2018·BioMed Research International·Abdel-Tawab H MossaNatarajan Chandrasekaran

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