LIPID-BASED DELIVERY SYSTEMS FOR IMPROVING THE BIOAVAILABILITY AND LYMPHATIC TRANSPORT OF A POORLY WATER-SOLUBLE LTB4 INHIBITOR

Ontazolast is a potent inhibitor (IC50 = 1 nm) of calcium ionophore A2 3187-stimulated leukotriene B-4 (LTB4) biosynthesis in human periphera l blood leukocytes. The compound is practically insoluble in water (0. 14 mu g/mL) and previous studies in animals have demonstrated extensiv e presystemic drug clearance through hepatic first-pass metabolism. Bi oavailability of a suspension formulation in rats was less than 1%, bu t increased to approximately 9% when administered as a 20% soybean oil -in-water emulsion, The emulsion formulation and three additional lipi d-based formulations were administered by gavage to conscious, minimal ly restrained rats in a novel, double-cannulated model to determine th e effects of formulation on systemic blood absorption and mesenteric l ymph transport of ontazolast. The bioavailability of ontazolast was si gnificantly and substantially enhanced by all of the lipid-based formu lations. While these formulations also significantly increased the amo unt of ontazolast transported by the lymph, the total amounts transpor ted were insufficient to account for the improvement in bioavailabilit y, which may be due to the elimination or reduction of the barriers of poor aqueous solubility and slow dissolution to absorption of ontazol ast from the gastrointestinal tract, or the effects of lipid on the ga strointestinal membrane permeability, transit time, or metabolism of o ntazolast. Semisolid SEDDS formulations, composed of Peceol and Geluci re 44/14, produced bioavailability similar to the emulsion formulation . The total amount of ontazolast transported by the lymph varied direc tly with the amount of concurrent triglyceride transport and appeared to be favored by formulations that prolong gastric emptying time or pr omote rapid absorption of ontazolast from the gastrointestinal tract.