Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Bloco J do Centro de Ciências da Saúde, sala 17, Universidade Federal do Rio de Janeiro, Cidade Universitária, Av. Carlos Chagas Filho, 373, CEP: 21941-912 Ilha do Fundão, Rio de Janeiro, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2010 Feb;381(2):147-52. doi: 10.1007/s00210-009-0483-z. Epub 2009 Dec 30.
Ivermectin is a large spectrum antiparasitic drug that is very safe at the doses actually used. However, as it is being studied for new applications that would require higher doses, we should pay attention to its effects at high concentrations. As micromolar concentrations of ivermectin have been reported to inhibit the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), we decided to investigate its putative inhibitory effect on other two important P-type ATPases, namely the Na(+) , K(+)-ATPase and H(+)/K(+)-ATPase. We first extended the data on SERCA, using preparations from rat enriched in SERCA1a (extensor digitorum longus) and 1b (heart) isoforms. Secondly, we tested the effect of ivermectin in two preparations of rat Na(+), K(+)-ATPase in order to appreciate its putative selectivity towards the alpha(1) isoform (kidney) and the alpha(2)/alpha(3) isoforms (brain), and in an H(+)/K(+)-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC(50) values (6-17 microM). With respect to the inhibition of the Na(+), K(+)-ATPase, ivermectin acts by a mechanism different from the classical cardiac glycosides, based on selectivity towards the isoforms, sensibility to the antagonistic effect of K(+) and to ionic conditions favoring different conformations of the enzyme. We conclude that ivermectin is a nonselective inhibitor of three important mammalian P-type ATPases, which is indicative of putative important adverse effects if this drug were used at high doses. As a consequence, we propose that novel analogs of ivermectin should be developed and tested both for their parasitic activity and in vitro effects on P-type ATPases.
伊维菌素是一种广谱抗寄生虫药物，在实际使用的剂量下非常安全。然而，由于它正在被研究用于新的应用，这些应用需要更高的剂量，我们应该注意它在高浓度下的作用。由于已经报道伊维菌素的微摩尔浓度可以抑制肌浆内质网 Ca(2+) -ATP 酶（SERCA），我们决定研究其对另外两种重要的 P 型 ATP 酶，即 Na(+), K(+)-ATP 酶和 H(+)/K(+)-ATP 酶的潜在抑制作用。我们首先扩展了关于 SERCA 的数据，使用来自富含 SERCA1a（伸趾长肌）和 1b（心脏）同工型的大鼠的制剂。其次，我们测试了伊维菌素在两种大鼠 Na(+), K(+)-ATP 酶制剂中的作用，以了解其对 alpha(1)同工型（肾脏）和 alpha(2)/alpha(3)同工型（大脑）的潜在选择性，以及在来自大鼠胃的 H(+)/K(+)-ATP 酶制剂中的作用。伊维菌素以相似的 IC(50)值（6-17 microM）抑制所有这些 ATP 酶。关于 Na(+), K(+)-ATP 酶的抑制作用，伊维菌素的作用机制不同于经典的强心苷，基于对同工型的选择性、对 K(+)拮抗作用的敏感性以及有利于酶不同构象的离子条件。我们得出结论，伊维菌素是非选择性抑制三种重要的哺乳动物 P 型 ATP 酶，这表明如果这种药物在高剂量下使用，可能会产生重要的不良反应。因此，我们建议开发和测试伊维菌素的新型类似物，不仅要测试它们的寄生虫活性，还要测试它们对 P 型 ATP 酶的体外作用。
