Influence of SLCO1B3 gene polymorphism on the pharmacokinetics of digoxin in terminal renal failure.
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.
Tsujimoto
Masayuki
M
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Japan.
Dan
Yukihiko
Y
Hirata
Sumio
S
Ohtani
Hisakazu
H
Sawada
Yasufumi
Y
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
D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D004077:Digoxin