Development, pharmacokinetics and mode of action of ivermectin.

Abstract

Microorganisms isolated from soil at the Kitasato Institute in Japan were tested in a variety of biological assays in Merck laboratories. One of the cultures was found to be active against a nematode parasite. It yielded a series of novel macrocyclic lactones, named avermectins, which proved active against a variety of nematode and arthropod parasites. An extensive programme of chemical modification resulted in the selection of ivermectin (22,23-dihydro-avermectin B1) for commercial development. The producing organism is a new actinomycete species, Streptomyces avermitilis. Strain selection and fermentation improvement were necessary to scale-up from laboratory flasks to 50,000 L fermentors. Using tritium-labelled drug it was shown that ivermectin is absorbed rapidly after oral or parenteral dosing and is excreted almost entirely in the faeces. Pharmacokinetic behaviour depends upon formulation and route of administration. Residues are highest in liver and fat and lowest in brain. Ivermectin has a high therapeutic index in target animals. Idiosyncratic toxicity has been observed in certain strains of dog at more than 8-fold the recommended dose of 6 ug/kg. Ivermectin causes paralysis in susceptible parasites. It is believed that this is the result of lowered cell membrane resistance produced by increased chloride ion influx.