In vitro enhancement of carvedilol glucuronidation by amiodarone-mediated altered protein binding in incubation mixture of human liver microsomes with bovine serum albumin

Makoto Sekimoto, Toru Takamori, Saki Nakamura, Masato Taguchi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1359-1363
Number of pages5
JournalBiological and Pharmaceutical Bulletin
Volume39
Issue number8
DOIs
StatePublished - 2016

Keywords

  • Amiodarone
  • Carvedilol
  • Drug interaction
  • Glucuronidation
  • Human liver microsome
  • Protein binding

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Fingerprint

Dive into the research topics of 'In vitro enhancement of carvedilol glucuronidation by amiodarone-mediated altered protein binding in incubation mixture of human liver microsomes with bovine serum albumin'. Together they form a unique fingerprint.

Cite this