title: Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure.
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.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Dan
authors.forename: Sumio
authors.initials: S
authors.lastname: Hirata
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D004077:Digoxin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency / Q000187:drug effects; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D016254:Mutagenesis, Insertional; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D051437:Renal Insufficiency / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D004077:Digoxin