INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, Toulouse, France.
PLoS Negl Trop Dis. 2012;6(11):e1883. doi: 10.1371/journal.pntd.0001883. Epub 2012 Nov 1.
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(-/-) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11-2.0 and 0.23-12.9 µmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD(50)) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(-/-) mice, LD(50) was 0.46 and 2.3 µmol/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 LD(50) were, in Mdr1ab(-/-) 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 concentrations are required for MOX toxicity than IVM. In rat α1β2γ2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA-induced response. The Hill coefficient was 1.52±0.45 for IVM and 0.34±0.56 for MOX (p<0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7±66.1 and 257.4±40.6%, respectively (p<0.05), showing that IVM causes a greater potentiation of GABA action on this receptor. Differences in the accumulation of IVM and MOX in the brain and in the interaction of IVM and MOX with GABA(A) receptors account for differences in neurotoxicity seen in intact and Mdr1-deficient animals. These differences in neurotoxicity of IVM and MOX are important in considering their use in humans.
伊维菌素（IVM）和莫昔克丁（MOX）等驱虫药在多种宿主物种中的毒性存在差异。进入大脑受到 P-糖蛋白（P-gp）外排转运蛋白的限制，而毒性则通过大脑 GABA(A)受体介导。本研究比较了 IVM 和 MOX 在体内的毒性及其与 GABA(A)受体在体外的相互作用。在皮下给予递增剂量（0.11-2.0 和 0.23-12.9 µmol/kg 用于 P-gp 缺陷型小鼠的 IVM 和 MOX 以及半致死剂量（LD(50)）用于野生型小鼠）后，评估药物毒性。在 14 天内评估存活情况。在 Mdr1ab(-/-) 小鼠中，IVM 和 MOX 的 LD(50)分别为 0.46 和 2.3 µmol/kg，表明 MOX 的毒性小于 IVM。在 P-gp 缺陷型小鼠中，MOX 的脑-血浆浓度比和进入大脑的速度均低于 IVM。在接近 LD(50)的剂量给药后，确定脑亚致死药物浓度分别为 Mdr1ab(-/-)和野生型小鼠中的 270 和 210 pmol/g 用于 IVM 和 830 和 740-1380 pmol/g 用于 MOX，表明 MOX 毒性需要更高的脑浓度比 IVM。在表达于非洲爪蟾卵母细胞的大鼠 α1β2γ2GABA 通道中，IVM 和 MOX 均为 GABA 诱导反应的变构激活剂。Hill 系数分别为 1.52±0.45 用于 IVM 和 0.34±0.56 用于 MOX（p<0.001），而 IVM 和 MOX 相对于单独 GABA 引起的最大增强分别为 413.7±66.1 和 257.4±40.6%（p<0.05），表明 IVM 引起 GABA 对该受体作用的更大增强。IVM 和 MOX 在大脑中的积累差异以及 IVM 和 MOX 与 GABA(A)受体的相互作用差异解释了在完整和 Mdr1 缺陷动物中观察到的神经毒性差异。IVM 和 MOX 的这些神经毒性差异在考虑它们在人类中的应用时很重要。
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