Fumagillin, a new P-glycoprotein-interfering agent able to modulate moxidectin efflux in rat hepatocytes.
We have tested the ability of two compounds licensed in veterinary medicine: fumagillin and diminazene diaceturate to increase intracellular moxidectin quantity in rat hepatocytes. These compounds significantly increased the quantity of 14C-moxidectin (expressed as area under the time curve concentrations) in cultured rat hepatocytes by 44% and 65% for diminazene and fumagillin treatments respectively. In addition, we have tested these drugs for their interference with P-glycoprotein (P-gp) function in porcine kidney epithelial cells transfected with murine mdr1a (Mdr1a-LLCPK1). We examined the intracellular accumulation of rhodamine 123 (Rho 123) as a functional test to evaluate the effects of these two drugs on P-gp activity. In this model, only fumagillin led to a marked intracellular accumulation of Rho 123. After transforming the data to express the results as a percentage of the accumulation in the presence of the P-gp inhibitor valspodar (VSP), the maximal Rho 123 accumulation was 47% of that with VSP for 100 microm fumagillin. The EC50, the concentration needed to determine 50% of the maximal effect was 34 microm. Fumagillin interacts with P-gp function and appears as a promising compound among registered drugs available, which may optimize the therapeutic use of macrocyclic lactones (MLs).
Dupuy
J
J
Laboratoire de Pharmacologie - Toxicologie, Chemin de Tournefeuille, Toulouse, France. jacques.dupuy@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*; D000818:Animals; D000871:Anthelmintics / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000494:pharmacology*; D004347:Drug Interactions; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism*; D018942:Macrolides / Q000493:pharmacokinetics; D051379:Mice; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D018942:Macrolides; D012717:Sesquiterpenes; C026211:fumagillin; C027837:moxidectin