Influence of SLCO1B3 Gene Polymorphism on the Pharmacokinetics of Digoxin in Terminal Renal Failure

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  • TSUJIMOTO Masayuki
    Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University
  • DAN Yukihiko
    Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University
  • HIRATA Sumio
    Department of Clinical Pharmacology, Graduate School of Pharmaceutical Sciences, Kumamoto University
  • OHTANI Hisakazu
    Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo
  • SAWADA Yasufumi
    Laboratory of Drug Informatics, Graduate School of Pharmaceutical Sciences, The University of Tokyo

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  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.<br>    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.<br>    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)).<br>    In conclusion, the insert-variant allele of the OATP1B3 gene may increase the C/D ratio of DX in HD patients.<br>

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