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Human metabolism of nebicapone (BIA 3-202), a novel catechol-o-methyltransferase inhibitor: characterization of in vitro glucuronidation.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Loureiro, Ana Isabel Bonifácio, Maria João Fernandes-Lopes, Carlos Almeida, Luis Wright, Lyndon Christopher Soares-Da-Silva, Patrício |
| Copyright Year | 2006 |
| Abstract | Nebicapone (BIA 3-202; 1-[3,4-dihydroxy-5-nitrophenyl]-2-phenylethanone), a novel catechol-O-methyltransferase inhibitor, is mainly metabolized by glucuronidation. The purpose of this study was to characterize the major plasma metabolites of nebicapone following p.o. administration of nebicapone to healthy volunteers, and to determine the human UDP-glucuronosyltransferase (UGT) enzymes involved in nebicapone glucuronidation. Plasma samples were collected as part of a clinical trial at different time points postdose and were analyzed for nebicapone and its metabolites using a validated method consisting of a solid-phase extraction, followed by high-performance liquid chromatography/mass spectrometry detection. The primary metabolic pathways of nebicapone in humans involve mainly 3-O-glucuronidation, the major early metabolite, and 3-O-methylation, the predominant late metabolite. Of the nine commercially available recombinant UGT enzymes studied (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15), only UGT1A9 exhibited high nebicapone glucuronosyltransferase specific activity (24.3 +/- 1.3 nmol/mg protein/min). UGT1A6, UGT1A7, UGT1A8, UGT1A10, UGT2B7, and UGT2B15 exhibited low activity (0.1-1.1 nmol/mg protein/min), and UGT1A1 and UGT1A3 showed extremely low activities (less than 0.03 nmol/mg protein/min). The results show that nebicapone is mainly glucuronidated in humans and that multiple UGT enzymes are involved in this reaction. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://dmd.aspetjournals.org/content/dmd/34/11/1856.full.pdf |
| PubMed reference number | 16790555v1 |
| Volume Number | 34 |
| Issue Number | 11 |
| Journal | Drug metabolism and disposition: the biological fate of chemicals |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acetylserotonin N-Methyltransferase Bia (butterflies) Catechol O-Methyltransferase Catechol-O-methyltransferase inhibitor Glucuronosyltransferase Liquid Chromatography Mass Spectrometry Metabolic Process, Cellular Methylation Methyltransferase Millimole per Kilogram Nanomole Recombinants UDP-Glucuronosyltransferase 1-7 UDP-Glucuronosyltransferase 2B15 UDP-glucuronosyltransferase, UGT1A8 UGT1A3 gene UGT1A6 gene UGT1A9 protein, human UGT2B7 gene bilirubin uridine-diphosphoglucuronosyl transferase 1A10 nebicapone |
| Content Type | Text |
| Resource Type | Article |
