Moxidectin and the avermectins: Consanguinity but not identity

Abstract

The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination.

Keywords: ATP binding cassette transporter; Avermectin; Ivermectin; Ligand-gated ion channels; Moxidectin; Nematode; Toxicity.

Graphical abstract

Fig. 1

Schematic filiations of macrocyclic lactones: from the soil bacteria to the therapeutic products.

Fig. 2

Interaction of ivermectin (IVM) with a glutamate-gated chloride channel (GluCl) as proposed by Hibbs and Gouaux (2011), showing moxidectin (MOX; maroon) superimposed over IVM (black). Note that while some of the interaction sites are shared in common between MOX and IVM (O10, O13, C18, C35 and C48), other interaction sites of IVM with the GluCl are either absent (C32, C33; both forming van der Waal (VDW) interactions with the GluCl in the case of IVM) due to the absence of any saccharide group in MOX, or are blocked/altered (O14; H-bond in the case of IVM) by the C23 methoxime group of MOX. The sites where interactions will be different for MOX compared with IVM are highlighted by a solid red circle. The 25-dimethly-butyl of MOX may also affect interaction with the GluCl (dashed red circle). IVM is a mixture of C25 ethyl (B1a; ∼10%) and C25 methyl (B1b; ∼90%). Against nematodes the B1b component is usually more potent than the B1a component, showing that the change from methyl to ethyl at this position affects potency. Thus it is likely that the 25-dimethyl-butyl group of MOX will also affect the interaction with a GluCl. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)