Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

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(−/−) 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 (LD50) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(−/−) mice, LD50 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 LD50 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.

Effects of third generation P-glycoprotein inhibitors on the sensitivity of drug-resistant and -susceptible isolates of Haemonchus contortus to anthelmintics in vitro

“…However, the cost of the new MDRIs will be important in determining their suitability for livestock applications. In addition, it will be important to consider the potential effects that the action of MDRIs on host animal ABC transport proteins may have on the interaction of anthelmintics with the host animal; for example, inhibition of host transporter proteins at the blood brain barrier could induce neurotoxic effects by IVM (Menez et al, 2012). These factors may impact on the practical use of MDRI/anthelmintic combination therapies.…”

Ion Channels and Drug Transporters as Targets for Anthelmintics

“…Macrocyclic lactones act as allosteric regulators; ivermectin binds to a transmembrane site distinct from the L-glutamate-binding site, and appears to stabilize an open-pore conformation [41]. Macrocyclic lactones also have activity against mammalian neuronal receptors, most notably the GABA A -gated channel [46]. Ivermectin is also a positive allosteric modulator at vertebrate neuronal nAchRs [47], while abamectin, which is used commercially in combination with derquantel, has recently been shown to non-competitively antagonize acetylcholine depolarizations and muscle contractions in Ascaris suum [48].…”

Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders

“…IVM, due to its lipophilic nature, should pass the blood brain barrier (BBB), but does not readily achieve high brain concentration, ostensibly due to its high efflux by P-glycoprotein (P-gp). Therefore, structural modifications that reduce its P-gp substrate recognition should increase brain concentration (Lespine et al, 2007; Menez et al, 2012) and should positively impact its ability to reduce ethanol intake (Yardley et al, 2012). Likewise, structural changes that alter its interaction with targeted brain receptors should also impact its efficacy in this regard.…”