Factors Affecting the Disposition of Ivermectin in the Target Species

It was the aim of the thesis to contribute to the understanding of the diverse factors involved in the pharmacokinetics of ivermectin, a very potent antiparasitic drug widely used in both human and veterinary medicine. Ivermectin is extensively eliminated in faeces as parent drug and less active metabolites, irrespective of species and route of administration. It is currently believed that biliary secretion is the major route for the elimination of parent ivermectin from blood. However, using validated in vitro (Caco-2 cells) and in situ (rat intestinal loops) models, we provide convincing evidence for an intestinal secretion of ivermectin from blood into the intestinal lumen. In the rat, intestinal secretion was even more important than biliary secretion in the overall elimination of parent ivermectin. These findings may initiate a re-appraisal of the disposition of ivermectin, particularly its distribution into the digestive tract, thereby allowing a better understanding of its clinical efficacy against gastrointestinal parasites. The above mentioned investigations also pointed towards the prominent role of P-glycoprotein (P-gp) in the intestinal secretion process, although other transport mechanisms (multidrug resistance-associated protein MRP2) may be involved. The relevance of these findings for veterinary target species was demonstrated by examining the P-gp function in cattle, sheep, goats, pigs and horses using a lymphocyte-based ex vivo model. P-gp activity was found in peripheral blood lymphocytes of all animal species studied, albeit at different levels. In addition, P-gp expression was shown in the intestines for all species. These results provide mechanistic support for the intestinal secretion of ivermectin and other P-gp substrates. Since wide interspecies variations in P-gp activity were observed, it can be expected that the contribution of this secretion mechanism may differ from one species to the other. Finally, we identified that physiological animal licking behaviour does obviously contribute to the disposition of ivermectin in cattle following topical application. Under our experimental conditions, 58-87% of the dose (500 mu-g/kg) applied topically over the back of cattle was actually ingested by licking, while only 10% of the dose was absorbed through the skin. Approximately 70% of the ingested ivermectin was not absorbed orally and transited directly into faeces, increasing by 5-fold the environmental burden of biologically active ivermectin. Our results suggest that the systemic exposure of topically-treated animals is related to their ability to lick themselves or each other. Furthermore, pharmacokinetic modeling was used to predict ivermectin disposition in cattle under various conditions of oral and/or percutaneous exposure. Our simulations suggest that non-treated cattle could get easily contaminated with ivermectin by social contact (allo-licking) with topically-treated animals present in the same herd. In conclusion, our findings may stimulate further investigations towards the contribution of intestinal secretion to the overall elimination of endectocides in target animal species. The examination of the role of P-gp and P-gp-like transporters (MRP2) in the relative disposition of different endectocides may be useful to understand differences in their pharmacokinetics and may support the development of new pharmaceutical formulations tailored towards individual compounds and target animal species.