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Rat and Rabbit Plasma Distribution of Free and Chylomicron-Associated BIRT 377, a Novel Small Molecule Antagonist of LFA-1-Mediated Cell Adhesion

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Abstract

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°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 collected 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.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Kishor M. Wasan, Manisha Ramaswamy & Lorilynne Holtorf

  2. Department of Bioassay, Biogen Inc., Cambridge, Massachusetts

    Andrew A. Jayaraj

  3. Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals Inc., Indianapolis, Indiana

    David J. Hauss

  4. Eli Lilly, Indianapolis, Indiana

    David J. Hauss

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  1. Kishor M. Wasan
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  2. Manisha Ramaswamy
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  4. Andrew A. Jayaraj
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Wasan, K.M., Ramaswamy, M., Holtorf, L. et al. Rat and Rabbit Plasma Distribution of Free and Chylomicron-Associated BIRT 377, a Novel Small Molecule Antagonist of LFA-1-Mediated Cell Adhesion. Pharm Res 18, 510–519 (2001). https://doi.org/10.1023/A:1011062512712

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