Fig. (2).

Brain penetration of macrocyclic lactones in wild-type mice (black columns), as well as in P-gp deficient mice (white columns) and dogs (grey columns). Ivermectin (IVM), moxidectin (MOX), eprinomectin (EPM), doramectin (DOR) and selamectin (SEL) were experimentally given to mdr1a(-/-) knockout mice (Schinkel et al. 1995a [43], 1994 [32]), mdr1a,b(-/-) double knockout mice (Geyer et al. 2008 [35], Kiki-Mvouaka et al. 2010 [44]), drug-sensitive CF-1 mice (Kwei et al. 1999 [39]), and ivermectin-sensitive Collies (Pulliam et al. 1985 [42]) or were therapeutically applied to MDR1(-/-) dogs at the following dosages: 200 µg/kg orally [32,35,39,42 left column,43], 200 µg/kg subcutaneously [44], 600 µg/kg orally [42 right column] and 1 mg/kg doramectin subcutaneously. Absolute drug concentrations in brain tissue were determined by liquid scintillation counting using the respective radiolabeled drugs [32,35,39,43] or by HPLC analysis [42,44]. Generally, drug concentrations in the brain were marginal in the wild-type mice and dramatically increased in the absence of P-gp. The two MDR1(-/-) dogs, "Sunny" and "Jake", were therapeutically given 1 mg/kg doramectin and developed severe neurotoxicosis. Both dogs died 5-6 days after treatment and were subjected to necropsy within 18 hours of death.