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.

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

“…Our data indicate that digoxin should not be used as a probe substrate for OATP1B3 in human hepatocyte systems. A previous clinical study suggested that an insert-variant allele of OATP1B3 was associated with an increase in the concentration/dose ratio of digoxin in patients on hemodialysis measured 62 to 72 h postdose (Tsujimoto et al, 2008). Although this finding appears to support a role for OATP1B3-mediated hepatic clearance in patients on hemodialysis, additional studies comparing this allele with the measured digoxin systemic clearance are needed to confirm these findings.…”

Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes

“…For example, metformin, digoxin, rosuvastatin, and sitagliptin are not (extensively) metabolized, but drug transporters have key roles in the disposition or efficacy of these compounds (see drugs labels at http://www.accessdata.fda.gov/ scripts/cder/drugsatfda/index.cfm). Metformin is a substrate for OCT1 and 2 [33,34], rosuvastatin is a substrate for OATP1B1 [35], digoxin is a Pgp substrate [36] and sitagliptin a substrate for OAT3 [37]. As remogliflozin etabonate and its metabolites are not strong inhibitors of transporters, there are expected to be no drug interactions between remogliflozin etabonate and these agents.…”

<b><i>ABCB1</i></b> and <b><i>SLCO1B3</i></b> Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population

“…SLCO1B3 genotype analysis of Ins/Del, 334T>G and 699G>A polymorphisms was performed using respectively 3 primers for exon 1, 3, and exon 6 as previously described [20]. Cycling conditions were an initial denaturation stage carried out at 94°C for 5 min.…”

“…Recently, 2 deletion polymorphisms from position (-28 to -11) and from position (-7 to -4) in exon 1 were apparently associated with the reduction of concentration-to-dose ratio of digoxin in terminal renal failure. Additionally, some studies have shown that SLCO1B3 334T>G (Ser112Ala; rs4149117) and 699G>A (Met233Ile; rs7311358) modulate the transport activity and may influence drugs pharmacokinetics including digoxin [19,20]. Nevertheless, Smith et al [21] (2007) have shown no association of drug pharmacokinetics with these genetic polymorphisms.…”

“…Nevertheless, Smith et al [21] (2007) have shown no association of drug pharmacokinetics with these genetic polymorphisms. Accordingly, results of the available data among Americans, Europeans, Africans, and Asians were varying and could not be confirmed [19,20,22,23]. Therefore, more studies are warranted to demonstrate the role of ABCB1 and SLCO1B3 gene polymorphisms in other populations in order to exhibit the wide interethnic differences that are present among the different groups.…”