title: Stereoselective metabolism of carvedilol by the beta-naphthoflavone-inducible enzyme in human intestinal epithelial Caco-2 cells.
abstract: Treatment of Caco-2 cells with beta-naphthoflavone (beta-NF) and 1alpha,25-dihydroxyvitamin D(3) (VD(3)) induces UDP-glucuronosyltransferases (UGTs) and cytochrome P450 (CYP) 3A4, respectively. In the present study, we evaluated the metabolism of carvedilol in beta-NF- and VD(3)-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 microM beta-NF for 3 d. In contrast, the treatment of Caco-2 cells with 250 nM VD(3) for 2 weeks did not induce a significant change in the metabolism of R- and S-carvedilol. The metabolism of carvedilol in beta-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 beta-NF-treated Caco-2 cells as compared with non-treated cells. These findings indicated that carvedilol was metabolized stereoselectively by the beta-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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Honda
authors.forename: Takako
authors.initials: T
authors.lastname: Shimizu
authors.forename: Masato
authors.initials: M
authors.lastname: Taguchi
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D001711:Biotransformation; D018938:Caco-2 Cells; D002117:Calcitriol / Q000494:pharmacology; D002227:Carbazoles / Q000493:pharmacokinetics*; D000077261:Carvedilol; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D011412:Propanolamines / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism; D019324:beta-Naphthoflavone / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D044950:Flavanones; D007527:Isoenzymes; D011412:Propanolamines; D012333:RNA, Messenger; D000077261:Carvedilol; C006680:baicalein; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; D002117:Calcitriol