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Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849) in rats

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Summary

Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849), a novel immunomodulatory agent, in rats was investigated. By co-chromatography with authentic samples, desmethylated (SM-8800)p-hydroxylated (SL-5512) and desmethylated-p-hydroxylated SM-8849 (SL-5515) were detected in the bile. Thermospray mass spectrometry (TSP-MS) analysis of five metabolites isolated from the bile revealed molecular ions of both conjugates (glucuronides and a sulfate) and their aglycones. Aglycone structures were determined by comparison of their product spectra with those of authentic standards. Further analyses of conjugation sites were carried out by1H-NMR including differential NOE. As a result, the sulfate of SL-5515 (5515-S), the N-glucuronides of SL-5512 and SM-8849 (5512-NG and 8849-NG, respectively), the glucuronide of SL-5512 (5512-G) and the O-glucuronide of 4-hydroxy-3-methoxy-SM-8849 (CatOMe-OG) were identified. In addition, N-methylthiourea was identified in urine by LC/MS/MS.

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References

  1. Abe C., Nishikaku F., Koga Y. (1991): Effects of SM-8849 on spontaneous arthritis in MRL/1 mice and type II collagen-induced arthritis in DBA/1J mice. Int. J. Immunother., 7, 1–8.

    CAS  Google Scholar 

  2. Nishikaku Y., Koga Y. (1991): Alteration in progression of murine autoimmune disease by treatment with a novel immunomodulator, SM-8849. Int. J. Immunopharmacol., 13, 445–454.

    Article  CAS  PubMed  Google Scholar 

  3. Nishikaku F., Koga Y. (1993): Suppression of murine collagen-induced arthritis by treatment with a novel thiazole derivative, SM-8849. Immunopharmacology, 25, 65–74.

    Article  CAS  PubMed  Google Scholar 

  4. Nishikaku F., Nakamura K., Kashiwazaki S., Koga Y. (1994): Prevention of spontaneous polyarthritis in NBZ/KN mice by treatment with a novel thiazole derivative, SM-8849. Drugs Exp. Clin. Res., 20, 85–92.

    CAS  PubMed  Google Scholar 

  5. Mico B.A., Swagzdis J.E., Federowicz D.A., Straub K. (1986): Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone. J. Pharm. Sci., 75, 929–933.

    Article  CAS  PubMed  Google Scholar 

  6. Rudwicz P., Straub K.M. (1986): Rapid structure elucidation of catecholamine conjugates with tandem mass spectrometry. Anal. Chem., 58, 2928–2934.

    Article  Google Scholar 

  7. Brashear W.T., Kuhnert B.R., Wei R. (1990): Structural determination of the conjugated metabolites of ritodrine. Drug Metab. Dispos., 18, 488–493.

    CAS  PubMed  Google Scholar 

  8. Jackson C.J., Hubbard J.W., McKay G., Cooper J.K., Hawes E.M., Midha K.K. (1991): Identification of phase I and phase II metabolites of fluphenazine in rat bile: intact glucuronide and sulfate conjugates. Drug Metab. Dispos., 19, 188–193.

    CAS  PubMed  Google Scholar 

  9. Yabuki M., Mine T., Iba K., Nakatsuka I., Yoshitake A. (1993): Metabolism of a tetrahydroaminoacridine derivative (SM-10888) in rat: structural analysis of an N-glucuronide of SM-10888 and an O-glucuronide of hydroxylated SM-10888 by FAB-MS/MS. Xenobiotica, 12, 1367–1375.

    Article  Google Scholar 

  10. Risdall P.C., Adams S.S., Crampton E.L., Marchant B. (1978): The disposition and metabolism of flurbiprofen in several species including man. Xenobiotica, 8, 691–704.

    Article  CAS  PubMed  Google Scholar 

  11. Maguire J.H., Kraus B.L., Buttler T.C., Dudly K.H. (1981): Stereochemical aspects of the metabolism of 5-ethyl-5-phenylhydantoin (NILVANOL) in the dog. Drug Metab. Dispos., 9, 393–401.

    CAS  PubMed  Google Scholar 

  12. Andersen J.V., Dalgaard L., Hansen S.H. (1989): Enzymic synthesis of two glucuronides of the hydroxyl oxazole GABA-agonist, THIP, and the in vivo glucuronidation of THIP in rat. Xenobiotica, 19, 1399–1406.

    Article  CAS  PubMed  Google Scholar 

  13. Chatfield D.H., Hunter W.H. (1973): The metabolism of acetamidothiazoles in the rat: 2-acetamido-2-acetamido-4-methyl-and 2-acetamido-4-phenyl-thiazole. Biochem. J., 134, 869–878.

    CAS  PubMed  Google Scholar 

  14. Chatfield D.H., Hunter W.H. (1973: The metabolism of acetamidothiazoles in the rat: 2-acetamido-4-chloromethylthiazole. Biochem. J., 134, 879–884.

    CAS  PubMed  Google Scholar 

  15. Mutlib A.E., Chui Y.C., Young L.M., Abbott F.S. (1992): Characterization of metabolites of xylazine produced in vivo and in vitro by LC/MS/MS and GC/MS. Drug. Metab. Dispos., 20, 840–848.

    CAS  PubMed  Google Scholar 

  16. Mizutani T., Yoshida K., Kawazoe S. (1994): Formation of toxic metabolites from thiabendazole and other thiazoles in mice: identification of thioamides as ring cleavage products. Drug Metab. Dispos., 22, 750–755.

    CAS  PubMed  Google Scholar 

  17. Liberti P., Stanbury J.B. (1971): The pharmacology of substances affecting the thyroid gland: Annu. Rev. Pharmacol., 11, 113–142.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Development Research Laboratories II, Sumitomo Pharmaceuticals Research Center, Osaka, Japan

    K. Iba

  2. Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, 3-chome Kasugade-Naka, Konohana-Ku, 554, Osaka, Japan

    M. Yabuki PhD, J. Shimakura, M. Ito, H. Kanamaru & I. Nakatsuka

Authors
  1. M. Yabuki PhD
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  2. J. Shimakura
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  3. M. Ito
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  4. H. Kanamaru
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  5. K. Iba
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  6. I. Nakatsuka
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Yabuki, M., Shimakura, J., Ito, M. et al. Metabolism of 4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (SM-8849) in rats. European Journal of Drug Metabolism and Pharmacokinetics 22, 25–33 (1997). https://doi.org/10.1007/BF03189781

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  • DOI: https://doi.org/10.1007/BF03189781

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