IN-VITRO STUDIES TO ELUCIDATE THE METABOLIC PATHWAY OF (-S-145, A THROMBOXANE-A(2) RECEPTOR ANTAGONIST, IN RATS - EVIDENCE FOR 2 INDEPENDENT PATHWAYS IN PEROXISOMAL BETA-OXIDATION())

The metabolism of (+)-S-145, a thromboxane A(2) receptor antagonist, w as investigated in vitro using isolated hepatocytes, liver homogenates , and subcellular fractions prepared from rats, The cofactor requireme nt and subcellular distribution of beta-oxidation and hydroxylation su ggested that the chain shortening of the carboxyl side chain of (+)-S- 145 was catalyzed by beta-oxidation enzyme systems in peroxisomes and hydroxylation at the C-5 and C-6 positions of the bicyclo ring was cat alyzed by monooxygenases in microsomes, respectively. In the initial s tage of metabolism of (+)-5-145, the potential of activation to its co enzyme A (CoA) thio ester was prominent, compared with that of the hyd roxylation, The resulting (+)-S-145-CoA was beta-oxidized. There seems to be two metabolic pathways in the metabolism of (+)-S-145-CoA. One is the biotransformation of (+)-S-145-CoA to bisnor-(+)-S-145 and tetr anor-(+)-S-145 in the beta-oxidation cycle, and the other is the reduc tion of (+)-S-145-CoA to dihydro-(+)-S-145-CoA by NADPH dependent Delt a(5)-reductase followed by beta-oxidation to dihydrobisnor-(+)-S-145, which was scarcely beta-oxidized to tetranor-(+)-S-145. finally, these beta-oxidized metabolites are hydroxylated by monooxygenases in micro somes at the 5- or 6-position of their bicycle ring, whereas beta-oxid ation activity of hydroxylated metabolites of (+)-S-145 was not observ ed in the light mitochondrial fraction nor in isolated hepatocytes.