| Abstrakt: |
Using a high-performance liquid chromatographic assay, these studies attempted to correlate circulating levels of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) with the serum interferon response induced in mice, cats, dogs, cattle, and rabbits. The order of greatest sensitivity for interferon induction by ABPP was mice greater than cats greater than dogs greater than cattle greater than rabbits. Experiments to date indicate that the circulating drug levels associated with a detectable interferon response were 10-15 microgram/ml (mice), 15-30 micrograms/ml (cats and dogs), and 30-50 micrograms/ml (cattle). Whereas rabbits produced large amounts (greater than 10(4) units/ml) of interferon when induced with Newcastle disease virus, we could not demonstrate unequivocally that rabbits were induced by ABPP even when circulating drug levels reached 50 micrograms/ml, or greater. We also observed differences in the pharmacokinetics of ABPP in the different species which may contribute to the differences described for the interferon responses. The data point out the need for cautious selection of animal models for preclinical efficacy evaluation and cautious extrapolation of data from preclinical studies to eventual clinical evaluation. |
