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Research ArticleArticle

Glucuronidation of a Sarpogrelate Active Metabolite Is Mediated by UDP-Glucuronosyltransferases 1A4, 1A9, and 2B4

Hyo-Ji Kim, Eun Sook Jeong, Kyung-Ah Seo, Kye Jung Shin, Yeon Jae Choi, Su-Jun Lee, Jong Lyul Ghim, Dong-Ryul Sohn, Jae-Gook Shin and Dong-Hyun Kim
Drug Metabolism and Disposition August 2013, 41 (8) 1529-1537; DOI: https://doi.org/10.1124/dmd.113.051862
Hyo-Ji Kim
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Eun Sook Jeong
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Kyung-Ah Seo
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Kye Jung Shin
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Yeon Jae Choi
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Su-Jun Lee
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Jong Lyul Ghim
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Dong-Ryul Sohn
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Jae-Gook Shin
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Dong-Hyun Kim
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea (H.-J.K., E.S.J., K.-A.S., S.-J.L., J.L.G., J.-G.S., and D.-H.K.); Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea (K.J.S. and Y.J.C.); and Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Chonan, South Korea (D.-R.S.)
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Abstract

Sarpogrelate is a selective serotonin 5-HT2A–receptor antagonist used to treat patients with peripheral arterial disease. This drug is rapidly hydrolyzed to its main metabolite (R,S)-1-[2-[2-(3–methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol (M-1), which is mainly excreted as a glucuronide conjugate. Sarpogrelate was also directly glucuronidated to an O-acyl glucuronide and a N-glucuronide by UDP-glucuronosyltransferases (UGTs) in human liver microsomes (HLMs). Since M-1 is pharmacologically more active than sarpogrelate, we examined glucuronidation of this metabolite in HLMs and characterized the UGTs responsible for M-1 glucuronidation. Diastereomers of O-glucuronide (SMG1 and SMG3) and a N-glucuronide (SMG2) were identified by incubation of M-1 with HLMs in the presence of uridine 5′-diphosphoglucuronic acid (UDPGA), and their structures were confirmed by nuclear magnetic resonance and mass spectrometry analyses. Two O-glucuronides were identified as chiral isomers: SMG1 as R-isomer and SMG3 as S-isomer. Using recombinant UGT enzymes, we determined that SMG1 and SMG3 were predominantly catalyzed by UGT1A9 and UGT2B4, respectively, whereas SMG2 was generated by UGT1A4. In addition, significant correlations were noted between the SMG1 formation rate and propofol glucuronidation (a marker reaction of UGT1A9; r = 0.6269, P < 0.0031), and between the SMG2 formation rate and trifluoperazine glucuronidation (a marker reaction of UGT1A4; r = 0.6623, P < 0.0015) in a panel of HLMs. Inhibition of SMG1, SMG2, and SMG3 formation by niflumic acid, hecogenin, and fluconazole further substantiated the involvement of UGT1A9, UGT1A4, and UGT2B4, respectively. These findings collectively indicate that UGT1A4, UGT1A9, and UGT2B4 are the major UGT isoforms responsible for glucuronidation of M-1, an active metabolite of sarpogrelate.

Footnotes

    • Received March 11, 2013.
    • Accepted May 23, 2013.
  • This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) [No. R13-2007-023-00000-0].

  • dx.doi.org/10.1124/dmd.113.051862.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Research ArticleArticle

UGT Isoforms Involved in Sarpogrelate Metabolite

Hyo-Ji Kim, Eun Sook Jeong, Kyung-Ah Seo, Kye Jung Shin, Yeon Jae Choi, Su-Jun Lee, Jong Lyul Ghim, Dong-Ryul Sohn, Jae-Gook Shin and Dong-Hyun Kim
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1529-1537; DOI: https://doi.org/10.1124/dmd.113.051862

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Research ArticleArticle

UGT Isoforms Involved in Sarpogrelate Metabolite

Hyo-Ji Kim, Eun Sook Jeong, Kyung-Ah Seo, Kye Jung Shin, Yeon Jae Choi, Su-Jun Lee, Jong Lyul Ghim, Dong-Ryul Sohn, Jae-Gook Shin and Dong-Hyun Kim
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1529-1537; DOI: https://doi.org/10.1124/dmd.113.051862
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