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Research ArticleArticle

METABOLISM OF 26,26,26,27,27,27-F6-1α,23S,25-TRIHYDROXYVITAMIN D3 BY HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A3*

Noriyuki Kasai, Toshiyuki Sakaki, Raku Shinkyo, Shin-ichi Ikushiro, Takashi Iyanagi, Miho Ohta and Kuniyo Inouye
Drug Metabolism and Disposition January 2005, 33 (1) 102-107; DOI: https://doi.org/10.1124/dmd.104.002303
Noriyuki Kasai
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Toshiyuki Sakaki
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Raku Shinkyo
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Shin-ichi Ikushiro
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Takashi Iyanagi
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Miho Ohta
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Kuniyo Inouye
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Abstract

26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxyvitamin D3 [F6-1α, 25(OH)2D3], which is now clinically used as a drug for secondary hyperparathyroidism, is a hexafluorinated analog of the active form of vitamin D3. Our previous studies demonstrated that CYP24A1 is responsible for the metabolism of F6-1α,25(OH)2D3 in the target tissues and that F6-1α,25(OH)2D3 was successively converted to F6-1α,23S,25(OH)3D3 and F6-23-oxo-1α,25(OH)2D3. In this study, we examined the metabolism of F6-1α,25(OH)2D3,F6-1α,23S,25(OH)3D3, and F6-23-oxo-1α,25(OH)2D3 by human UDP-glucuronosyltransferases (UGTs). Of these compounds, F6-1α,23S,25(OH)3D3 was remarkably glucuronidated both in human liver microsomes and in the recombinant system expressing human UGT. No significant interindividual differences were observed among 10 human liver samples. The recombinant system for 12 species of human UGTs revealed that F6-1α,23S,25(OH)3D3 glucuronidation was specifically catalyzed by UGT1A3. The information obtained in this study seems very useful to predict the metabolism and efficacy of vitamin D analogs in human bodies before clinical trials. In addition, note that for the first time a possible probe substrate for UGT1A3 has been found.

Footnotes

  • This work was partly supported by Health Science research grants from the Ministry of Health, Labor and Welfare of Japan, and a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan.

  • doi:10.1124/dmd.104.002303.

  • ABBREVIATIONS: F6-1α,25(OH)2D3, 26,26,26,27,27,27,-hexafluoro-1α,25-dihydroxyvitamin D3; UGT, UDP-glucuronosyltransferase; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry.

    • Received September 14, 2004.
    • Accepted October 20, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (1)
Drug Metabolism and Disposition
Vol. 33, Issue 1
1 Jan 2005
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Research ArticleArticle

METABOLISM OF 26,26,26,27,27,27-F6-1α,23S,25-TRIHYDROXYVITAMIN D3 BY HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A3*

Noriyuki Kasai, Toshiyuki Sakaki, Raku Shinkyo, Shin-ichi Ikushiro, Takashi Iyanagi, Miho Ohta and Kuniyo Inouye
Drug Metabolism and Disposition January 1, 2005, 33 (1) 102-107; DOI: https://doi.org/10.1124/dmd.104.002303

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Research ArticleArticle

METABOLISM OF 26,26,26,27,27,27-F6-1α,23S,25-TRIHYDROXYVITAMIN D3 BY HUMAN UDP-GLUCURONOSYLTRANSFERASE 1A3*

Noriyuki Kasai, Toshiyuki Sakaki, Raku Shinkyo, Shin-ichi Ikushiro, Takashi Iyanagi, Miho Ohta and Kuniyo Inouye
Drug Metabolism and Disposition January 1, 2005, 33 (1) 102-107; DOI: https://doi.org/10.1124/dmd.104.002303
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