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标题：Stereoselective Metabolism of Carvedilol by the β-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells
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作者：Kazuya Ishida ; Mutsuko Honda ; Takako Shimizu 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2007
卷号：30
期号：10
页码：1930-1933
DOI：10.1248/bpb.30.1930
出版社：The Pharmaceutical Society of Japan
摘要：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 μ M β-NF for 3 d. In contrast, the treatment of Caco-2 cells with 250 n M 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.
关键词：Caco-2 cell;carvedilol;UDP-glucuronosyltransferase;β-naphthoflavone;1α,25-dihydroxyvitamin D3