Influence of transporter polymorphisms on digoxin serum concentrations: a systematic review and meta-analysis

Polymorphisms in transporter (P-gp, OATP) genes affect digoxin pharmacokinetics and are crucial for predicting toxicity due to its narrow therapeutic index. However, evidence regarding their effects on digoxin serum concentrations remain inconsistent. This systematic review and meta-analysis aimed to evaluate the influence of transporter polymorphisms on digoxin serum concentrations. A systematic search of EBSCOhost, Scopus, PubMed, Web of Science and ClinPGx was conducted up to May 2025. Study quality was evaluated using the Newcastle-Ottawa Scale. Mean differences with 95% confidence intervals were calculated for digoxin serum concentrations (Cmax, AUC, and SDC) using a random-effects model. Statistical heterogeneity was assessed using the I2 statistic, and subgroup analyses were performed. Nineteen eligible studies were identified. A significant association was observed between ABCB1 C3435T polymorphism and elevated digoxin Cmax across multiple genetic models, with the largest effect observed between codominant T/T versus C/C (MD: 0.40 ng/mL; 95% CI: 0.14–0.66). Conversely, opposite associations were observed in the Japanese population, where C allele carriers had higher digoxin AUC0–4 hr. The ABCB1 C3435T polymorphism influences digoxin serum concentrations and may inform genotype-guided therapy. However, the limited number of studies in meta-analysis warrants further well-designed studies. This systematic review and meta-analysis was not registered in any protocol registry. Digoxin is a medicine used to manage heart failure and atrial fibrillation. However, it must be prescribed carefully because small changes in its plasma concentration can cause digoxin toxicity and, in serious cases, sudden cardiac death. This review looked at whether the genetic differences in drug transporters, such as ABCB1, SLCO1B1, and SLCO1B3, affect digoxin levels in the blood. We found that people carrying the T allele of the ABCB1 C3435T often have high digoxin serum concentrations compared to those without the variant. However, Japanese people with the variant showed lower digoxin serum levels. Other variants did not show significant associations. This suggests that people with the ABCB1 C3435T variant may have a higher risk of digoxin toxicity. Genetic testing for this variant could help doctors identify patients who need close monitoring and dose adjustments. This information could make digoxin treatment safer and more effective for the patients. Larger studies involving different populations are still needed to better understand how other variants might influence digoxin levels.