Lipid-like properties and pharmacology of the anthelmintic macrocyclic lactones

Introduction: Broad-spectrum antiparasitic macrocyclic lactones (MLs) are the principal nematicides used today, but drug resistance compromises the efficiency of ML-based therapy. Drug action in the parasite is essential for the effectiveness. Thus, to meet the needs of sustainable control of nematodes, the challenge is to maintain an effective drug concentration in the host tissues where parasites locate. This requires knowledge of the site of action of the drug, and processes that govern the pharmacokinetics of MLs in the host and in the parasites. These processes are primarily biotransformation, distribution, storage in fat, and elimination via ATP-binding cassette (ABC) transporters. Areas covered: This article describes how MLs are lipid-like compounds that differ in chemical substituents and in physicochemical properties. Furthermore, the degree of drug lipophilicity influences affinity for fat tissues and for transporters and possibly for target receptors. This opinion highlights how the structural particularities of widely used representative MLs impact on drug kinetics. Expert opinion: Optimizing the efficacy of MLs relies on the choice of the drug on the degree of lipophilicity, taking into account the host species, the location of the parasites, and alterations in lipid status. Furthermore, lipid-based formulations can be used to improve intestinal drug absorption. Inhibiting ABC transporter offers an additional option for increasing ML bioavailability.