Ivermectin is a nonselective inhibitor of mammalian P-type ATPases

Abstract

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 Ca²⁺-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 α₁ isoform (kidney) and the α₂/α₃ isoforms (brain), and in an H⁺/K⁺-ATPase preparation from rat stomach. Ivermectin inhibited all these ATPases with similar IC₅₀ values (6–17 µM). 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.