Metabolic profiling of a novel antithrombotic compound, S002‐333 and enantiomers: metabolic stability, species comparison and in vitro–in vivo extrapolation

ConclusionThe in vitro CLint values for S002‐333, S004‐1032 and S007‐1558 were 0.027 ± 0.005, 0.025 ± 0.004 and 0.036 ± 0.005 ml/min/mg, respectively, in PHLM, indicating that S007‐1558 was the most metabolically unstable of the three. The LM of other species showed similar results. A common surrogate species to humans for S002‐333 and enantiomers was predicted as rabbit where the extrapolated hepatic clearance (CLH) did not show a significant difference to the in vivo CLH values. However, none of the species closely mimic humans with respect to the proportion of major metabolites (M‐1–M‐4) formed in vitro. Likewise, the CLH values were also predicted in humans for S002‐333 and enantiomers using various mathematical models. During analysis, there was no chiral inversion evident among the individual isomers throughout in vitro and in vivo experiments. In conclusion, the in vitro results indicate a prominent role of phase I metabolism in the degradation of S002‐333 and enantiomers and predict rabbit as an alternative species to conduct further safety and efficacy studies. Copyright © 2016 John Wiley & Sons, Ltd.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research