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.
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.
Yamaguchi
Y
Y
Department of Drug Metabolism and Disposition, Shionogi and Co., Ltd., Osaka, Japan.
Baba
T
T
Touchi
A
A
Matsubara
T
T
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D003065:Coenzyme A / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008830:Microbodies / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011448:Prostaglandin Antagonists / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism*
D001643:Bridged Bicyclo Compounds; D005229:Fatty Acids, Monounsaturated; D011448:Prostaglandin Antagonists; D017482:Receptors, Thromboxane; C056566:S 145; D013928:Thromboxane A2; D003065:Coenzyme A