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

ConclusionIn‐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 S007‐1558, the most metabolically unstable among the three. LM of other species showed similar results. Common surrogate species to humans for S002‐333 and enantiomers was predicted as rabbit where extrapolated hepatic clearance (CLH) did not show significant difference with in‐vivo CLH values. However, none of the species closely mimic to humans with respect to proportion of major metabolites (M‐1 through M‐4) formed in‐vitro. Likewise, 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 individual isomers throughout in‐vitro and in‐vivo experiments. In conclusion, in‐vitro results indicate prominent role of phase‐I metabolism in degradation of S002‐333 and enantiomers and predict rabbit as an alternative species to conduct further safety and efficacy studies. This article is protected by copyright. All rights reserved.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research