ABSTRACT
BACKGROUND: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. METHODS: ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. RESULTS: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. CONCLUSION: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.
Subject(s)
Atrial Fibrillation/metabolism , Digoxin/pharmacokinetics , Organic Anion Transporters, Sodium-Independent/genetics , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Aged , Aged, 80 and over , Digoxin/blood , Female , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Solute Carrier Organic Anion Transporter Family Member 1B3 , TunisiaABSTRACT
Activity of the renin-angiotensin Aldosterone system is increased in patients with heart failure (HF). The Angiotensinogen gene and specifically M235T polymorphism has been linked to susceptibility to hypertension, coronary heart disease and atrial fibrillation. Its role in heart failure is not yet sufficiently demonstrated. The aim of the present study was to assess the association between rs699 (M235T) polymorphism and heart failure in terms of diagnosis and prognosis. We included all patients over 20 years old consulting in the Emergency Department for acute dyspnea. According to the results of the B-type natriuretic peptide (BNP level), patients were divided into two groups: HF and non-HF group. DNA study was performed for all subjects and their genotypes were identified as TT, CT or CC. Mortality was followed for one year. We included 234 patients. We found the diagnosis of HF in 73 patients out of 160 (45%). Our results showed that the frequency of the T allele was higher in HF group patients than in non-HF group (69% vs. 33%, P<0.01). Patients carrying the TT and CT genotypes had a higher proportion of HF than those carrying the CC genotype (respectively 53% and 31% vs. 15%, P<0.01). According to multivariate analysis, TT genotype presented the highest risk of HF (OR=4.9 95% CI: 2.12-9.1) and the highest risk of death (OR=6.45 95% CI: 3.6-16.4) compared to the other two genotypes. The current study suggests that M235T polymorphism might be associated with increased risk of both HF and death.
