Page 576 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Macrocyclic Lactone Endectocides Chapter | 43 543

VetBooks.ir Blood FIGURE 43.7 Cartoon of normal p-glyco-
protein function within the blood brain barrier
(BBB). P-glycoprotein is a transmembrane
pump (gray trapezoids) located on the apical
(blood-facing) side of endothelial cells that
T.J.
T.J. form the BBB. These endothelial cells are
joined through tight junctions (T.J.) that pre-
vent diffusion of substances between the cells.
(1) P-glycoprotein substrates (diamonds) dif-
fuse into and out of the endothelial cells
through the lipid bilayer of the cell membrane.
(2) Substrates within the cell or cell membrane
ATP ADP are taken up by the p-glycoprotein molecule,
+ an active process requiring ATP for energy.
P i (3) Once taken up by the p-glycoprotein, sub-
strates are ejected back into the bloodstream.
1 2 3
Defects in p-glycoprotein structure and/or
function can result in increased concentrations
of substrates within the endothelial cell, and
egress of substrates out the basal side of the
cell into the brain. Please see color plate
section.
Brain

suggesting that more than one genotypic abnormality may
TABLE 43.1 Dog Breeds in Which ABCB1 Mutations result in a similar phenotypic expression.
Have Been Identified Although MLs undergo some metabolism, the majority
are excreted unchanged in the feces via the bile. This
Australian shepherd
Border collie excretion into the intestine results in reabsorption and
Collie enterohepatic recycling of up to 20% of the total dose of
English shepherd ML administered (Lanusse et al., 2009). The fact that par-
German shepherd enterally administered ML ultimately ends up being
Longhaired whippet secreted into the bile and thereby enters the intestinal tract
McNab
Old English sheepdog to undergo some degree of enterohepatic recycling largely
Shetland sheepdog explains the efficacy of injected MLs against intestinal
Silken windhound parasites. Up to 95% of an ML dose is excreted
Wa ¨ller unchanged in the feces and the half-lives for the various
White Swiss shepherd
MLs are in the range of days to weeks rather than hours.
Reported by Geyer, J., Klintsch, S., Meerkamp, K., et al., 2007. Detection Half-lives for the various MLs vary widely depending on
of the nt230 (del4) MDR1 mutation in white Swiss shepherd dogs: case formulation, dose administered and species, as well as the
reports of doramectin toxicosis, breed predisposition, and microsatellite
analysis. J. Vet. Pharmacol. Therap. 30:482 485; Mosher, C.M., Court, relative amount of body fat (Lo et al., 1985; Fink and
M.H., 2010. Comparative and veterinary pharmacogenomics. In Porras, 1989; Lallemand et al., 2007).
Comparative and Veterinary Pharmacology, Handbook of Experimental
Pharmacology, Cunningham F, Elliott J, Lees P (eds). Springer-Verlag, There have been many ML pharmacokinetic/toxicoki-
Berlin, pp. 50 78. netic studies conducted in dogs, cats, sheep, goats, cattle,
horses, and pigs (Tway et al., 1981; Lo et al.,1985;
Prichard et al., 1985; Alvinerie et al., 1987, 1993; Marriner
xenobiotics has been demonstrated in dogs with the et al., 1987; Bogan and McKeller, 1988; Toutain et al.,
ABCB1 mutation, pharmacokinetic studies have shown no 1988, 1997; Fink and Porras, 1989; Scott and McKeller,
significant differences in oral bioavailability or elimination 1991; Godber et al., 1995; Sarasola et al., 2002; Gupta
between dogs with mutant ABCB1 and wild-type dogs et al.,2005). It is evident from many of these studies that
(Mealey et al., 2010). Affected dogs develop clinical effects ivermectin and its derivatives are excreted in the milk.
of ML toxicosis at levels that do not cause clinical signs in
dogs with normal P-GP. Recently, a novel insertion muta- MECHANISM OF ACTION
tion in the ABCB1 gene was found to be associated with
ivermectin sensitivity in a border collie that lacked the pre- The MLs exert their toxic actions through their high affin-
viously described deletion mutation (Han et al., 2010), ity for ligand-gated chloride channels, particularly those