The pharmacodynamics of ivermectin in sheep and cattle

Abstract

The concentrations of ivermectin in the gastrointestinal tract of sheep and cattle were determined after subcutaneous administration of ivermectin. Ivermectin was not detected (limit of detection 1 ng/ml) in abomasal and ruminal fluids either after a normal therapeutic dose of 200 micrograms/kg or even at an increased dose of 2000 micrograms/kg. It was also not detected in abomasal and ruminal fluids of a sheep infected with the abomasal parasite Ostertagia circumcincta. However, ivermectin was detectable at similar concentrations in abomasal mucus and in small intestinal mucus. Excretion of ivermectin was high in bile but the concentrations in small intestinal mucus, distal and proximal to the bile duct opening, were similar. It is hypothesized that the low efficacy of ivermectin against small intestinal nematodes compared with abomasal nematodes is not due to differences in ivermectin concentrations in the predilection sites but is probably due to tachyphylaxis in the nematodes allowing the small intestinal nematodes to re-establish before they have left their predilection site. Ivermectin was excreted in the milk of ewes at concentrations similar to those in plasma. Lambs suckling ivermectin-treated ewes received about 4% of a normal therapeutic dose (200 micrograms/kg) via the milk.

Intestinal Secretion Is a Major Route for Parent Ivermectin Elimination in the Rat

“…Our study suggests the existence of an intestinal route of elimination of ivermectin in human and in target animal species. The observations reported in cattle by Bogan and McKellar (1988) support this hypothesis. Following subcutaneous administration, ivermectin was found at rather high concentrations in small intestinal mucus with no significant difference between mucus distal and proximal to the bile duct opening.…”

“…Ivermectin is extensively eliminated by the fecal route as parent drug and metabolites, regardless of the species and of the route of administration, with less than 2% excreted in the urine (Campbell, 1985). As the biliary concentration of ivermectin is substantially higher than that in plasma (Bogan and McKellar, 1988;Lifschitz et al, 2000), it has been assumed that biliary secretion was the major pathway of elimination of the parent drug. The study of Hennessy et al (2000), performed in sheep with the structural analog doramectin, supported this hypothesis.…”

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

“…This explanation, however, is difficult to conciliate with our results, since the unabsorbed fraction of ingested ivermectin was fully recovered in the faeces of the lickers. Moreover, several studies argue for the stability of ivermectin in rumen fluids in cattle and sheep [3,6] and show that there is rather an extensive adsorption of ivermectin to the digesta particulates of the rumen [1]. Our model stipulates that the fraction of drug which is not absorbed in compartment GIT 1 will not be absorbed later in compartment GIT 2.…”

Synopsis

“…Neither is the efficacy against intestinal nematodes fully explainable with AUC as these parasites also may encounter the proportion of orally given drug that is not absorbed (McKellar et al, 1991). On the other hand, ivermectin was not detected at all in abomasal fluid of sheep after sc injection at 200 or even 2000 u g/kg (Bogan & McKellar, 1988).…”