Stereoselective metabolism of carvedilol by the β-naphthoflavone-inducible enzyme in human intestinal epithelial caco-2 cells

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  • Ishida Kazuya
    Graduate School of Pharmaceutical Sciences, University of Toyama
  • Honda Mutsuko
    Graduate School of Pharmaceutical Sciences, University of Toyama
  • Shimizu Takako
    Graduate School of Pharmaceutical Sciences, University of Toyama
  • Taguchi Masato
    Graduate School of Pharmaceutical Sciences, University of Toyama
  • Hashimoto Yukiya
    Graduate School of Pharmaceutical Sciences, University of Toyama

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タイトル別名
  • Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells
  • Stereoselective metabolism of carvedilol by the v naphthoflavone inducible enzyme in human intestinal epithelial caco 2 cells

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Treatment of Caco-2 cells with β-naphthoflavone (β-NF) and 1α,25-dihydroxyvitamin D3 (VD3) induces UDP-glucuronosyltransferases (UGTs) and cytochrome P450 (CYP) 3A4, respectively. In the present study, we evaluated the metabolism of carvedilol in β-NF- and VD3-treated Caco-2 cells. The metabolism of R-carvedilol was not significant in non-treated Caco-2 cells, whereas S-carvedilol was significantly metabolized in the cells. The metabolism of R- and S-carvedilol was significantly increased by the treatment of Caco-2 cells with 50 μM β-NF for 3 d. In contrast, the treatment of Caco-2 cells with 250 nM VD3 for 2 weeks did not induce a significant change in the metabolism of R- and S-carvedilol. The metabolism of carvedilol in β-NF-treated Caco-2 cells was markedly inhibited by a substrate of UGTs, baicalein. In addition, the expression of UGT1A1, 1A6, and 1A9 mRNA was increased in β-NF-treated Caco-2 cells as compared with non-treated cells. These findings indicated that carvedilol was metabolized stereoselectively by the β-NF-inducible enzyme in Caco-2 cells. The UGT1A subfamily in intestinal epithelial cells may be partly responsible for first-pass (presystemic) metabolism of the drug.

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