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Fumagillin, a new P‐glycoprotein‐interfering agent able to modulate moxidectin efflux in rat hepatocytes 1
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.1365-2885.2006.00780.x
Subject(s) - fumagillin , p glycoprotein , intracellular , moxidectin , pharmacology , efflux , chemistry , rhodamine 123 , transfection , biology , biochemistry , microbiology and biotechnology , ivermectin , gene , multiple drug resistance , angiogenesis , antibiotics , zoology , cancer research
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 14 C‐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 μ m fumagillin. The EC 50 , the concentration needed to determine 50% of the maximal effect was 34 μ m . 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).