Rat and rabbit plasma distribution of free and chylomicron-associated BIRT377, a novel small molecule antagonist of LFA-1-mediated cell adhesion

Purpose. The objectives of this study are to determine the plasma distribut ion of free and chylomicron-associated BIRT 377 within rats and rabbits. Methods. For the rat studies free and chylomicron-associated BIRT 377 was i ncubated in plasma from CD 1 non-fasted rats for 60 minutes at 37 degreesC. Following incubation the plasma was separated into its lipoprotein and lip oprotein-deficient plasma (LPDP) fractions by three different methods and a nalyzed for BIRT 377 content by HPLC. For the rabbit studies New Zealand fa sted white rabbits, (3 kg; n = 4) were administered an intravenous dose of free BIRT 377 (1 mg/kg). Following administration, serial blood samples wer e obtained and the plasma was analyzed for BIRT 317. The plasma collected a t the 0.083-h time point was separated into each of its lipoprotein fractio ns 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. 415 +/- 0.4% of the ori ginal chylomicron-associated drug concentration incubated was recovered wit hin the lipoprotein-rich fraction. The percentage of drug recovered within the TRL fraction was significantly greater following the incubation of chyl omicron-associated BIRT 377 compared to free BIRT 377. Ln addition, BIRT 37 7 apparently follows a two-compartment pharmacokinetic model following sing le intravenous dose administration to rabbits. Conclusions. These finding suggest that plasma lipoprotein binding of BIRT 377 is evident and may be a factor in evaluating the pharmacological fate o f this drug when administered to patients that exhibit changes in their pla sma lipoprotein lipid.