Insight into stereoselective disposition of enantiomers of a potent antithrombotic agent, S002-333 following administration of the racemic compound to mice

S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide], a potent antithrombotic agent developed by CSIR-CDRI, is a racemic mixture of two enantiomers (S004-1032 (R)-isomer and S007-1558 (S)-isomer). Despite extensive research, little is known about the pharmacokinetics of S002-333 enantiomers. Given that mouse is an established model for anti-platelet/antithrombotic activity and interspecies differences exists in the direction of stereoselectivity in pharmacokinetic processes, we investigated the pharmacokinetic disposition of S002-333 enantiomers in mice. Whereas the pharmacokinetics of S002-333 was non-stereoselective after intravenous (i.v.) administration, substantial stereoselectivity was observed after oral administration of the racemate. The oral AUC0 − ∞ of (R)-isomer (1228.21 ± 97.55 h ∗ ng/mL) was higher than that of (S)-isomer (861.55 ± 182.07 h ∗ ng/mL) whereas it was comparable after i.v. administration. The absolute oral bioavailability of (R)-isomer was ~ 1.7 times higher than that of its antipode. On incubating the racemic mixture or individual isomers with mice liver microsomes, (S)-isomer depleted significantly faster than (R)-isomer. Thus, low absolute oral bioavailability of (S)-isomer in comparison to (R)-isomer could be associated to stereoselective hepatic metabolism of (S)-isomer. Furthermore, no metabolic interaction between the enantiomers was observed. Tissue distribution analysis revealed that the highest amount of the enantiomers was localized in small intestine and liver which could be due to first pass metabolism in these organs. Stereoselectivity in the distribution of S002-333 was observed in liver, kidney, spleen and brain; however no significant differences between the plasma protein binding of the enantiomers were observed. The information revealed in the present work might prove valuable in deciding the development of S002-333 as racemic mixture and/or single enantiomer.

155