Efficacy in sheep and pharmacokinetics in cattle that led to the selection of Eprinomectin as a topical endectocide for cattle

Eprinomectin (MK-397 or 4 ''-epi-acetylamino-4 ''-deoxy-avermectin B-1) is a novel avermectin selected for development as a topical endectocide for all cattle, including lactating cows. The initial efficacy assessments were made in sheep to identify subclasses of the avermectin/milbemycins that possessed inherent activity against a spectrum of nematode parasites. This included examination of several hundred analogs each given orally to a single sheep experimentally infected with a range of parasitic nematodes. Representatives of several subclasses, most notably the 4 ''-epi-amino avermectin B-1 subclass, were identified as possessing potent, broad-spectrum activity against the endoparasites, whereas subclasses such as those with a variety of synthetic substitutions at C-4a or oximes at C-5 were among the least potent. Eprinomectin, a member of the 4 ''-epi-amino subclass, possessed potent activity against the range of nematodes when tested at 0.025 mg kg(-1) per os. Milk and plasma concentration profiles were also made for these and other selected avermectin/milbemycins following topical administration to lactating dairy-cattle. The molecular structure of each compound had a significant effect on the milk to plasma ratio, but the ratio of each was constant over time, implying an equilibrium between the 2 compartments. Compounds that were saturated at the C-22,23 band had milk to plasma ratios greater than or equal to 1.0, whereas those unsaturated at this bond were generally less than or equal to 1.0. The milk to plasma ratio of eprinomectin was less than or equal to 0.2. Therefore, not only is eprinomectin the most potent broad spectrum avermectin/milbemycin identified to date, but it also possesses one of the lowest milk partitioning coefficients in this class of antiparasitics.