Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. I. Investigation of potential experimental and mechanistic explanations

SB-265123 is a novel αvβ3 (the vitronectin receptor) antagonist. Previous rat studies with it revealed an apparent absolute oral bioavailability (Fapp) of greater than 100%. The present studies were conducted to investigate the potential causes for this observation.Of 49 SB-265123 analogues evaluated in rat using an identical experimental design, Fapp>100% was observed for 22 of them, suggesting that the observed Fapp>100% with SB-265123 was not anomalous. All 22 compounds had clearances 100% were not recorded for all low-clearance analogues.Using SB-265123 as a model to investigate potential artefacts, it was demonstrated that using a chiral assay did not decrease Fapp. Additionally, qualitative sample analysis demonstrated that no metabolites were present in the plasma that could interfere with the liquid chromatography coupled with tandem mass spectrometry detection assay. The high Fapp was also dose-order-, delivery system- and vehicle-independent, and was not affected ...