PT  - JOURNAL ARTICLE
AU  - Y Yamaguchi
AU  - T Baba
AU  - A Touchi
AU  - T Matsubara
TI  - In vitro studies to elucidate the metabolic pathway of (+)-S-145, a thromboxane A2 receptor antagonist, in rats. Evidence for two independent pathways in peroxisomal beta-oxidation.
DP  - 1995 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1195--1201
VI  - 23
IP  - 11
4099  - http://dmd.aspetjournals.org/content/23/11/1195.short
4100  - http://dmd.aspetjournals.org/content/23/11/1195.full
SO  - Drug Metab Dispos1995 Nov 01; 23
AB  - The metabolism of (+)-S-145, a thromboxane A2 receptor antagonist, was investigated in vitro using isolated hepatocytes, liver homogenates, and subcellular fractions prepared from rats. The cofactor requirement and subcellular distribution of beta-oxidation and hydroxylation suggested 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 catalyzed by monooxygenases in microsomes, respectively. In the initial stage of metabolism of (+)-S-145, the potential of activation to its coenzyme A (CoA) thio ester was prominent, compared with that of the hydroxylation. 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 tetranor-(+)-S-145 in the beta-oxidation cycle, and the other is the reduction of (+)-S-145-CoA to dihydro-(+)-S-145-CoA by NADPH dependent delta 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 microsomes at the 5- or 6-position of their bicyclo ring, whereas beta-oxidation activity of hydroxylated metabolites of (+)-S-145 was not observed in the light mitochondrial fraction nor in isolated hepatocytes.