title: Efficacy in sheep and pharmacokinetics in cattle that led to the selection of eprinomectin as a topical endectocide for cattle.
abstract: Eprinomectin (MK-397 or 4"-epi-acetylamino-4"-deoxy-avermectin B1) 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 B1 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 bond had milk to plasma ratios > or = 1.0, whereas those unsaturated at this bond were generally < or = 1.0. The milk to plasma ratio of eprinomectin was < or = 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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Shoop
authors.forename: P
authors.initials: P
authors.lastname: DeMontigny
authors.forename: D W
authors.initials: DW
authors.lastname: Fink
authors.forename: J B
authors.initials: JB
authors.lastname: Williams
authors.forename: J R
authors.initials: JR
authors.lastname: Egerton
authors.forename: H
authors.initials: H
authors.lastname: Mrozik
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: B J
authors.initials: BJ
authors.lastname: Skelly
authors.forename: M J
authors.initials: MJ
authors.lastname: Turner
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000900:Anti-Bacterial Agents; D002417:Cattle; D002418:Cattle Diseases; D015195:Drug Design; D005260:Female; D006801:Humans; D007559:Ivermectin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007774:Lactation; D018942:Macrolides / Q000493:pharmacokinetics; D015394:Molecular Structure; D009348:Nematoda / Q000187:drug effects; D009349:Nematode Infections / Q000188:drug therapy / Q000662:veterinary*; D012756:Sheep; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D018942:Macrolides; D007559:Ivermectin; C019264:avermectin; C101434:eprinomectin; C027837:moxidectin