Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure

Masayuki Tsujimoto, Yukihiko Dan, Sumio Hirata, Hisakazu Ohtani, Yasufumi Sawada

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Digoxin (DX) is mainly excreted unchanged in the urine. In patients undergoing hemodialysis (HD patients), the relative contribution of hepatic elimination is increased. DX is a substrate of OATP1B3 (SLCO1B3), expressed on the sinusoidal membranes of hepatocytes in humans. Therefore, we investigated the relationship between SLCO1B3 gene polymorphisms and the value of trough concentration-to-dose ratio (C/D ratio) of DX in HD patients. We investigated two deletion polymorphisms in complete linkage disequilibrium (-28 to -11 and -7 to -4) and two SNPs in complete linkage disequilibrium (T334G and G699A). Blood was sampled 62-72 hours after the oral administration of DX. The C/D ratio of DX was lower in patients with the deletion allele than in those homozygous for the insertion allele, and was lower in patients with the 334T/669G allele than in those homozygous for the 334G/699A allele, although the differences were not statistically significant. The C/D ratio of DX was significantly higher in patients with homozygous for the insert-variant allele (median: 121.8 (ng/mL)/(mg/week/kg), range: 92.5-259.4 (ng/mL)/(mg/week/kg) than in others (median: 93.4 (ng/mL)/(mg/ week/kg), range: 66.5-154.3 (ng/mL)/(mg/week/kg)). In conclusion, the insert-variant allele of the OATP1B3 gene may increase the C/D ratio of DX in HD patients.

Original languageEnglish
Pages (from-to)406-411
Number of pages6
JournalDrug Metabolism And Pharmacokinetics
Volume23
Issue number6
DOIs
Publication statusPublished - 2008 Jan 1
Externally publishedYes

Keywords

  • Digoxin
  • Genetic polymorphism
  • Non-renal clearance
  • Organic anion transporting polypeptide (OATP) 1B3
  • SLC transporters
  • Terminal renal failure

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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