relative neurotoxicity of ivermectin and moxidectin in mdr1ab (？？) mice and effects on mammalian gaba(a) channel activity相对神经毒性的伊维菌素和该药mdr1ab( )小鼠和影响哺乳动物gaba(a)频道活动.pdfVIP

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (2/ 2) Mice and Effects on Mammalian GABA(A) Channel Activity ´ ´ 1,2 1,2 3 1,2 Cecile Menez , Jean-Franc¸ois Sutra , Roger Prichard , Anne Lespine * ´ 1 INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, Toulouse, France, 2 Universite de Toulouse, INP, UMR1331, Toxalim, Toulouse, France, 3 Institute of Parasitology, McGill University, Montreal, Canada Abstract The anthelmintics ivermectin (IVM) and moxidectin (MOX) display differences in toxicity in several host species. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A) receptors. This study compared the toxicity of IVM and MOX in vivo and their interaction with GABA(A) receptors in vitro. Drug toxicity was assessed in Mdr1ab(2/ 2) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11–2.0 and 0.23–12.9 mmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD50) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab( 2/ 2) mice, LD50 was 0.46 and 2.3 mmol/kg for IVM and MOX, respectively, demonstrating that MOX was less toxic than IVM. In P-gp-deficient mice, MOX had a lower brain-to-plasma concentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administration of doses close to LD50 were, in Mdr1ab( 2/ 2) and wild-type mice, respectively, 270 and 210 pmol/g for IVM and 830 and 740–1380 pmol/g for MOX, indicating that higher brain c