Related Experiment Video
Updated: Jul 6, 2026
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration
Albert-Jan L H J Aarnoudse1, Jeanne P Dieleman, Loes E Visser
1Department of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands.
Pharmacogenetics and Genomics
|March 13, 2008
Summary
Common genetic variations in the ABCB1 gene are linked to higher digoxin levels in elderly individuals. This study clarifies the impact of ABCB1 polymorphisms on digoxin pharmacokinetics in a large population.
Area of Science:
- Pharmacogenomics
- Clinical Pharmacology
Background:
- Digoxin is a cardiac glycoside commonly prescribed for heart failure and arrhythmias.
- The ATP-binding cassette B1 (ABCB1/MDR1) transporter plays a crucial role in digoxin pharmacokinetics.
- Previous studies on ABCB1 polymorphisms and digoxin levels have yielded contradictory results, often due to small sample sizes and single-dose kinetics.
Purpose of the Study:
- To investigate the association between ABCB1 gene polymorphisms and digoxin blood concentrations in a large cohort of elderly European individuals using chronic digoxin therapy.
- To clarify the impact of specific ABCB1 single nucleotide polymorphisms (SNPs) and haplotypes on digoxin serum levels.
Main Methods:
- A prospective, population-based cohort study (Rotterdam Study) involving individuals aged 55 years and above who were chronic digoxin users.
- Collection of digoxin serum levels from regional hospitals and laboratories.
- Genotyping of ABCB1 SNPs (1236C-->T, 2677G-->T/A, 3435C-->T) using Taqman assays on peripheral blood DNA.
- Statistical analysis using linear regression models to assess the association between ABCB1 genotypes/haplotypes and digoxin levels, adjusting for confounders.
Main Results:
- Data from 195 participants (56.4% women, mean age 79.4 years) were analyzed.
- All three studied ABCB1 variants (1236C-->T, 2677G-->T, 3435C-->T) showed a significant association with increased serum digoxin concentration (0.18-0.21 microg/l per additional T allele).
- The TTT haplotype (1236-2677-3435) demonstrated a stronger association with higher digoxin levels (0.26 mug/l), suggesting a combined effect of linked SNPs.
Conclusions:
- Common ABCB1 variants (1236C-->T, 2677G-->T, 3435C-->T) and the TTT haplotype are associated with elevated digoxin serum concentrations in elderly European digoxin users.
- These findings contribute to understanding the genetic basis of digoxin variability in a general population.
- The results highlight the importance of considering ABCB1 genotype in managing digoxin therapy to optimize patient outcomes.
Related Concept Videos
01:16Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
01:26Heart Failure Drugs: Inotropic Agents
Positive inotropic agents are commonly used as the first line of treatment for heart failure. One such agent is digoxin, derived from the genus Digitalis, which has been known for centuries but effectively utilized since 1785. However, these cardiac glycosides can have potentially toxic effects due to their mechanism of action, which involves inhibiting Na+/K+-ATPase and increasing contractility. Digoxin is absorbed orally and distributed in various tissues, including the CNS. It has a long...
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
01:29Factors Affecting Protein-Drug Binding: Patient-Related Factors
Protein-drug binding, a pivotal aspect of pharmacokinetics, is subject to considerable variability influenced by an array of patient-related factors. The intricate interplay of age, individual differences, and pathological conditions significantly impact the binding dynamics and subsequent pharmacological effects.
Age stands as a key determinant in protein-drug binding. Neonates, characterized by low albumin content, experience heightened concentrations of unbound drugs such as phenytoin and...
Age stands as a key determinant in protein-drug binding. Neonates, characterized by low albumin content, experience heightened concentrations of unbound drugs such as phenytoin and...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
01:20Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers
Class IV antiarrhythmic drugs, such as verapamil and diltiazem, block calcium channels. They primarily affect the heart, slowing the conduction in calcium-dependent tissues like the SA and AV nodes. These drugs manage reentrant supraventricular tachycardia (SVT) and reduce ventricular rate in atrial flutter/fibrillation.
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...