Rat and rabbit plasma distribution of free and chylomicron-associated BIRT 377, a novel small molecule antagonist of LFA-1-mediated cell adhesion.
OBJECTIVE
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.
Wasan
K M
KM
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
Ramaswamy
M
M
Holtorf
L
L
Jayaraj
A A
AA
Hauss
D J
DJ
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002914:Chylomicrons / Q000378:metabolism*; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D048289:Imidazolidines; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry; D008074:Lipoproteins / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats
C400461:BIRT 377; D002914:Chylomicrons; D007093:Imidazoles; D048289:Imidazolidines; D007166:Immunosuppressive Agents; D008074:Lipoproteins; D016169:Lymphocyte Function-Associated Antigen-1