<i>In Vitro</i> Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin
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- Sekimoto Makoto
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- Takamori Toru
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- Nakamura Saki
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
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- Taguchi Masato
- Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
Bibliographic Information
- Other Title
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- In Vitro Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin
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Abstract
<p>Carvedilol is mainly metabolized in the liver to O-glucuronide (O-Glu). We previously found that the glucuronidation activity of racemic carvedilol in pooled human liver microsomes (HLM) was increased, R-selectively, in the presence of amiodarone. The aim of this study was to clarify the mechanisms for the enhancing effect of amiodarone on R- and S-carvedilol glucuronidation. We evaluated O-Glu formation of R- and S-carvedilol enantiomers in a reaction mixture of HLM including 0.2% bovine serum albumin (BSA). In the absence of amiodarone, glucuronidation activity of R- and S-carvedilol for 25 min was 0.026, and 0.51 pmol/min/mg protein, and that was increased by 6.15 and 1.60-fold in the presence of 50 µM amiodarone, respectively. On the other hand, in the absence of BSA, or when BSA was replaced with human serum albumin, no enhancing effect of amiodarone on glucuronidation activity was observed, suggesting that BSA played a role in the mechanisms for the enhancement of glucuronidation activity. Unbound fraction of S-carvedilol in the reaction mixture was greater than that of R-carvedilol in the absence of amiodarone. Also, the addition of amiodarone caused a greater increase of unbound fraction of R-carvedilol than that of S-carvedilol. These results suggest that the altered protein binding by amiodarone is a key mechanism for R-selective stimulation of carvedilol glucuronidation.</p>
Journal
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- Biological and Pharmaceutical Bulletin
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Biological and Pharmaceutical Bulletin 39 (8), 1359-1363, 2016
The Pharmaceutical Society of Japan
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Details 詳細情報について
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- CRID
- 1390001204631355904
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- NII Article ID
- 130005254702
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- NII Book ID
- AA10885497
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- ISSN
- 13475215
- 09186158
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- NDL BIB ID
- 027523117
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- PubMed
- 27476943
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
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- Abstract License Flag
- Disallowed