Effects of uremic serum and uremic toxins on hepatic uptake of digoxin

Masayuki Tsujimoto, Yuri Kinoshita, Sumio Hirata, Masaki Otagiri, Hisakazu Ohtani, Yasufumi Sawada

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Not only the renal clearance but also the hepatic clearance of drugs varies with the progression of renal failure. The aim of this study was to investigate the effects of human uremic serum and various uremic toxins on the hepatic uptake of digoxin (DX), a drug mainly excreted into bile in patients with severe renal failure, using isolated rat and human hepatocytes as model systems. Uremic serum inhibited the uptake of DX into rat hepatocytes in a concentration-dependent manner, whereas normal serum did not affect the uptake. In addition, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol (PC) concentration dependently inhibited the uptake. CMPF and PC at the concentration of 400 μΜ, which is within the plasma concentration range attained in patients with renal failure, inhibited the uptake of DX into rat hepatocytes by 27% and 23%, respectively. In human hepatocytes, 10% uremic serum, 400 μΜ CMPF, and 400 μΜ PC inhibited the uptake of DX by 23.3%, 23.4%, and 28.2%, respectively. In conclusion, our results suggest that hepatic uptake of DX is likely to be inhibited by uremic toxins, such as CMPF and PC, present in the serum of patients with renal failure.

Original languageEnglish
Pages (from-to)576-582
Number of pages7
JournalTherapeutic Drug Monitoring
Volume30
Issue number5
DOIs
Publication statusPublished - 2008 Oct

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Keywords

  • Digoxin
  • Hepatic uptake
  • Renal failure
  • Uremic toxin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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