Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice
Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice
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DOI：
10.1111/j.1365-2885.2008.01007.x
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发表时间：
2009-02-01
影响因子：
1.3
通讯作者：
Petzinger, E.
中科院分区：
文献类型：
--
作者：
Geyer, J.;Gavrilova, O.;Petzinger, E.
P-糖蛋白由多药耐药基因 (MDR1) 编码，通过血脑屏障上 ATP 驱动的外排机制高度限制伊维菌素进入大脑。然而，在携带 MDR1 纯合突变的狗中，伊维菌素会在大脑中积聚，引发严重的神经中毒症状，甚至死亡。与伊维菌素相比，塞拉菌素在治疗 MDR1 突变狗时更安全，这表明塞拉菌素通过 P-糖蛋白跨血脑屏障的转运方式不同。为了测试这一点，我们将赛拉菌素应用于 mdr1 缺陷型 mdr1a,b(-/-) 敲除小鼠和野生型小鼠。与伊维菌素相比，在静脉内、口服和皮肤点滴应用后分析脑渗透、器官分布和血浆动力学。我们发现，在体内，这两种大环内酯化合物都是 P-糖蛋白的底物，并且与野生型小鼠相比，在治疗剂量为 12 mg/kg 塞拉菌素和 0.2 mg/kg 伊维菌素时，这些化合物在 mdr1a,b(-/-) 敲除小鼠的大脑中强烈积聚。然而，在缺乏P-糖蛋白的情况下，塞拉菌素的蓄积程度（5-10倍）比伊维菌素（36-60倍）低得多。这可以解释塞拉菌素在 MDR1 突变狗中具有更广泛的安全范围。在 mdr1a,b 突变小鼠的肝脏、肾脏和睾丸中，伊维菌素和塞拉菌素的积累量不到野生型小鼠的四倍。应用研究中还包括乳腺癌抗性蛋白（Bcrp）缺陷型bcrp（-/-）敲除小鼠，但与野生型小鼠相比，伊维菌素或塞拉菌素的脑浓度或器官分布没有差异。这表明Bcrp不是体内这些大环内酯化合物在血脑屏障处的相关外排载体。
P-glycoprotein, which is encoded by the multi-drug resistance gene (MDR1), highly restricts the entry of ivermectin into the brain by an ATP-driven efflux mechanism at the blood-brain barrier. In dogs with a homozygous MDR1 mutation though, ivermectin accumulates in the brain and provokes severe signs of neurotoxicosis and even death. In contrast to ivermectin, selamectin is safer in the treatment of MDR1 mutant dogs, suggesting that selamectin is transported differently by P-glycoprotein across the blood-brain barrier. To test this, we applied selamectin to mdr1-deficient mdr1a,b(-/-) knockout mice and wild-type mice. Brain penetration, organ distribution, and plasma kinetics were analyzed after intravenous, oral, and dermal spot-on application in comparison with ivermectin. We found that in vivo both macrocyclic lactone compounds are substrates of P-glycoprotein and that these strongly accumulate in the brain of mdr1a,b(-/-) knockout mice compared with wild-type mice at therapeutic doses of 12 mg/kg selamectin and 0.2 mg/kg ivermectin. However, selamectin accumulates to a much lesser degree (5-10 times) than ivermectin (36-60 times) in the absence of P-glycoprotein. This could explain the broader margin of safety of selamectin in MDR1 mutant dogs. In liver, kidney, and testes, ivermectin and selamectin accumulated less than four times as much in mdr1a,b mutant mice as in wild-type mice. Breast cancer resistance protein (Bcrp)-deficient bcrp(-/-) knockout mice were also included in the application studies, but showed no differences in brain concentrations or organ distribution of either ivermectin or selamectin compared with wild-type mice. This indicates that Bcrp is not a relevant efflux carrier for these macrocyclic lactone compounds in vivo at the blood-brain barrier.