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 journalArticlepeer-review

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
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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