Regional-dependent intestinal absorption and meal composition effects on systemic availability of LY303366, a lipopeptide antifungal agent, in dogs.

ABSTRACT

Low oral bioavailability and a negative meal effect on drug plasma levels motivated studies on formulation and meal composition effects on the absorption of LY303366, a poorly water-soluble, semisynthetic, cyclic peptide antifungal drug. Solid drug particle size and meal composition studies were evaluated in beagle dogs. Canine regional absorption studies were also carried out utilizing surgically implanted intestinal access ports, and Caco-2 studies were performed to evaluate drug candidate intestinal permeability. Particle size and Caco-2 data indicate that drug permeability limitations to absorption are more important than dissolution rate limits. Caco-2 cell-associated LY303366 approached 10% of incubation concentration that is in the range of the oral bioavailability of the drug. Canine regional absorption studies showed that the extent of LY303366 absorption following duodenal administration was similar to that following oral administration. Significantly lower drug plasma levels were obtained following administration through a colonic access port, a result consistent with poor membrane permeation. Administration of drug with meals of mixed composition, as well as simple fat and protein meals, resulted in significant reductions in AUC(0-48h) compared with results from fasted dogs. In contrast, carbohydrate meals did not reduce drug plasma levels compared to controls. Intravenous pretreatment with devazepide, a cholecystokinin (CCK) antagonist that blocks canine biliary secretion, did not reverse the negative effect of the fat meal on LY303366. Taken together, the results from the present study suggest that membrane-permeability-limited absorption is the cause of the observed regionally dependent absorption of LY303366 in the dog and that the observed negative meal effects depend on composition but are independent of biliary secretion.