Development of an in vivo preclinical screen model to estimate absorption and bioavailability of xenobiotics.

The purpose of this study was to develop an in vivo screening method for rapid preclinical characterization of absorption and bioavailability of large numbers of compounds. This effort involved several steps. First, a pharmacokinetic characterization of a reference compound was conducted in the monkey. These data were used to verify theoretical calculations of a maximal portal dose-normalized area under the concentration-time curve. Next, a monkey screen was implemented using mixtures of up to five compounds each (i.e., cassettes) to estimate the bioavailability of approximately 200 compounds. Cassettes were administered as a single intraduodenal dose to a single monkey followed by simultaneous portal and systemic blood sampling. Definitive studies were then conducted to determine absolute bioavailability of 14 of these compounds. The studies with the reference compound demonstrated that the theoretical methodology based on a single intraduodenal dose with portal and systemic sampling provided consistent estimates of bioavailability. In the screen studies, approximately 75% of the test compounds were excluded from further evaluation due to poor absorption. Of the 14 compounds selected for follow-up evaluation from both well and poorly absorbed compounds, the absolute bioavailability of 10 of them were correctly classified from the screening data. The remaining 4 compounds were false positives, which showed low bioavailability; no false negatives were encountered. This approach allows for a rapid and reliable screen to evaluate absorption and bioavailability using a single dose in a preclinical model.