Identification of Metabolites of a New Thromboxane A2 Receptor Antagonist, S-1452, in Rats.

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  • MIZOJIRI Kenji
    Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • NORIKURA Ryo
    Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • YOSHIMORI Takeo
    Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • NAKANISHI Machiko
    Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • IWATANI Kouji
    Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • TERUI Yoshihiro
    Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • KIKUCHI Junko
    Shionogi Research Laboratories, Shionogi & Co., Ltd.
  • NAKAGAWA Yuzo
    Shionogi Research Laboratories, Shionogi & Co., Ltd.

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  • 新規トロンボキサンＡ２受容体きっ抗薬（Ｓ‐１４５２）のラットにおける代謝物の同定

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The metabolism of S-1452, calcium (5Z)-7-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate hydrate, a new TXA2 receptor antagonist, in rats was studied. Twelve unconjugated metabolites including the unchanged free acid of S-1452, (+)-S-145, and three α-chain-shortended metabolites, bisnor-, dihydrobisnor- and tetranor-(+)-S-145, and four pairs of their regioisomeric metabolites, hydroxylated at the 5- or 6-position of the bicyclo ring, were isolated from plasma after oral administration of 14C-S-1452 or unlabelled S-1452. Two of the hydroxylated metabolites, 5-OH-tetranor- and 6-OH-tetranor-(+)-S-145, were also isolated from urine. Furthermore, four taurine-conjugated metabolites, (+)-S-145, bisnor-(+)-S-145, dihydrobisnor-(+)-S-145 and tetranor-(+)-S-145 taurine, were isolated from bile. The structures of these metabolites were identified by means of GC/MS, LSIMS and 1H-NMR analyses in comparison with their synthesized reference compounds. The stereochemistry of 6-OH-(+)-S-145, the exo configuration of its hydroxy group, was confirmed by comparison of its retention time on HPLC with those of endo and exo reference standards. Other hydroxylated metabolites also were considered to be of the exo configulation. Tentative metabolic pathways in rats are presented and discussed.

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