The interaction between moxidectin and MDR transporters in primary cultures of rat hepatocytes.
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.
Dupuy
J
J
Laboratoire de Pharmacologie-Toxicologie, INRA, BP 3, Toulouse, France. jdupuy@toulouse.inra.fr
Lespine
A
A
Sutra
J F
JF
Alvinerie
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000871:Anthelmintics / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism*; D018942:Macrolides / Q000493:pharmacokinetics; D008297:Male; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000871:Anthelmintics; D018942:Macrolides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C489249:Abcg2 protein, rat; C027837:moxidectin