ELUCIDATION OF METABOLIC PATHWAY OF THROMBOXANE A2 RECEPTORANT ANTAGONIST, (+)-S-145, IN RAT

Abstract

Metabolism of (+)-S-145 was investigated within vitro studies to elucidate the metabolic pathway and responsible enzymes therein. Co-factor requirements and subcellular distribution indicated that a-side chain of (+)-S-145 was β-oxidized by peroxisomal enzymes, and that hydroxylation at C-5 or C-6 position of bicyclo-ring was catalyzed by cytochrome P-450s in microsomes. Results of these studies revealed that the most of (+)-S 145 incorporated into liver was activated to its acyl-CoA ester, and that β-oxidation was major pathway in metabolism of (+)-S-145. In peroxisome, there were two independent pathways in β-oxidation, thus (+)-S 145-CoA was generally β-oxidized to Bisnor-(+)S-145 and Tetranor-(+)-S 145, meanwhile its a-side chain was saturated by Δ5-reduction to form DH(+)-S-145 by NADPH dependent manner, then it was β-oxidized to DH-bisnor-(+)-S-145. As OH-(+)S-145 could never be n-oxidized, it was concluded that OH-Tetranor-(+)-S-145, one of major metabolites in vivo, was produced in the hydroxylation of Tetranor-(+)-S-145 catalyzed mainly by P-450 3A1/2.