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

Low oral bioavailability and a negative meal effect on drug plasma levels m otivated studies on formulation and meal composition effects on the absorpt ion of LY303366, a poorly water-soluble, semisynthetic, cyclic peptide anti fungal drug. Solid drug particle size and meal composition studies were eva luated in beagle dogs. Canine regional absorption studies were also carried out utilizing surgically implanted intestinal access ports, and Caco-2 stu dies were performed to evaluate drug candidate intestinal permeability. Particle size and Caco-2 data indicate that drug permeability limitations t o absorption are more important than dissolution rate limits. Caco-2 cell-a ssociated LY303366 approached 10% of incubation concentration that is in th e range of the oral bioavailability of the drug. Canine regional absorption studies showed that the extent of LY303366 absorption following duodenal a dministration was similar to that following oral administration. Significan tly 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 f at and protein meals, resulted in significant reductions in AUC(0-48h) comp ared with results from fasted dogs. In contrast, carbohydrate meals did not reduce drug plasma levels compared to controls. Intravenous pretreatment w ith devazepide, a cholecystokinin (CCK) antagonist that blocks canine bilia ry secretion, did not reverse the negative effect of the fat meal on LY3033 66. Taken together, the results from the present study suggest that membran e-permeability-limited absorption is the cause of the observed regionally d ependent absorption of LY303366 in the dog and that the observed negative m eal effects depend on composition but are independent of biliary secretion. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.