Rat and rabbit plasma distribution of free and chylomicron-associated BIRT 377, a novel small molecule antagonist of LFA-1-mediated cell adhesion.

PURPOSE: The objectives of this study are to determine the plasma distribution of free and chylomicron-associated BIRT 377 within rats and rabbits. METHODS: For the rat studies free and chylomicron-associated BIRT 377 was incubated in plasma from CD 1 non-fasted rats for 60 minutes at 37 degrees C. Following incubation the plasma was separated into its lipoprotein and lipoprotein-deficient plasma (LPDP) fractions by three different methods and analyzed for BIRT 377 content by HPLC. For the rabbit studies New Zealand fasted white rabbits (3 kg; n=4) were administered an intravenous dose of free BIRT 377 (1 mg/kg). Following administration, serial blood samples were obtained and the plasma was analyzed for BIRT 377. The plasma conected at the 0.083-h time point was separated into each of its lipoprotein fractions and analyzed for BIRT 377. RESULTS: 37.8 +/- 1.2% of the original drug amount incubated in rat plasma was recovered within the lipoprotein-rich fraction. 41.5 +/- 0.4% of the original chylomicron-associated drug concentration incubated was recovered within the lipoprotein-rich fraction. The percentage of drug recovered within the TRL fraction was significantly greater following the incubation of chylomicron-associated BIRT 377 compared to free BIRT 377. In addition, BIRT 377 apparently follows a two-compartment pharmacokinetic model following single intravenous dose administration to rabbits. CONCLUSIONS: These findings suggest that plasma lipoprotein binding of BIRT 377 is evident and may be a factor in evaluating the pharmacological fate of this drug when administered to patients that exhibit changes in their plasma lipoprotein lipid.

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 A23187-stimulated leukotriene B4 (LTB4) biosynthesis in human peripheral blood leukocytes. The compound is practically insoluble in water (0.14 microgram/mL) and previous studies in animals have demonstrated extensive presystemic drug clearance through hepatic first-pass metabolism. Bioavailability of a suspension formulation in rats was less than 1%, but increased to approximately 9% when administered as a 20% soybean oil-in-water emulsion. The emulsion formulation and three additional lipid-based formulations were administered by gavage to conscious, minimally restrained rats in a novel, double-cannulated model to determine the effects of formulation on systemic blood absorption and mesenteric lymph transport of ontazolast. The bioavailability of ontazolast was significantly and substantially enhanced by all of the lipid-based formulations. While these formulations also significantly increased the amount of ontazolast transported by the lymph, the total amounts transported were insufficient to account for the improvement in bioavailability, which may be due to the elimination or reduction of the barriers of poor aqueous solubility and slow dissolution to absorption of ontazolast from the gastrointestinal tract, or the effects of lipid on the gastrointestinal membrane permeability, transit time, or metabolism of ontazolast. Semisolid SEDDS formulations, composed of Peceol and Gelucire 44/14, produced bioavailability similar to the emulsion formulation. The total amount of ontazolast transported by the lymph varied directly with the amount of concurrent triglyceride transport and appeared to be favored by formulations that prolong gastric emptying time or promote rapid absorption of ontazolast from the gastrointestinal tract.