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ABCB1 polymorphism and acenocoumarol safety in patients with valvular atrial fibrillation

Abstract

BACKGROUND:

Oral anticoagulant drugs (AD) are commonly used to treat patients with thromboembolic diseases. The ADs have narrow therapeutic index and wide pharmacokinetic and pharmacodynamic interindividual variability. Some genetic variations could influence interindividual variability in response to AD. Acenocoumarol (AC) is a coumarin, vitamin K derivate with antagonistic activity, used as anticoagulant therapy mainly in Central Europe and Latin America. P – glycoprotein (PGP), a transporter encoded by the ABCB1 gene, plays a major role in the drug disposition [1]. PGP is expressed in normal tissues, where it performs a defensive role against potentially toxic substances in intestinal cells and endothelial cells of the brain capillary endothelium. ABCB1 – is highly polymorphic, C3435T polymorphism in exon 26 has been associated with the expression of PGP [2]. There is some evidence that PGP could influence coumarin sensitivity.

OBJECTIVE:

To assess effects of the ABCB1 pilymorphisms on safety profile and dosing regimen of acenocoumarol in the patients with valvular atrial fibrillation.

METHODS:

50 patients (34 male and 16 female), 40–70 years of age were included. All patients received acenocoumarol at doses of 1–6 mg daily with a target international normalized ratio (INR) of 2.0 to 3.0. Genotyping for polymorphism marker C3435T of ABCB1 gen was performed using PCR and RFLP (restriction fragment length polymorphisms) techniques. Statistics were performed by Fishers exact tests. All enrolled patients provided written informed consent.

RESULTS:

Genotype CC was found in 10 patients (20%), genotype CT in 25 patients (50%) and genotype TT in 15 patients (30%). In the CC group (n = 10) bleeding was found in 1 patient (2%). There were 19 patients (38%) with bleedings in combined group of CT and TT genotype (p = 0.0366). We compared the average doses of acenocoumarol in groups identified according to their genotypes: CC (3.45 mg/day), CT (2.64 mg/day), TT (3.07 mg/day) and found no significant differences.

CONCLUSIONS:

ABCB1 CT and TT genotypes were found to be significantly associated with higher risk of bleeding. There was no influence of ABCB1 polymorphisms on dosing regimens of acenocoumarol.

Conflict of interest statement

The authors report no conflicts of interest.

References

1 

Ling V 1997 Multidrug resistance: Molecular mechanisms and clinical relevance Cancer Chemotherapy and Pharmacology 401S3S810.1007/s002800051053

2 

Hoffmeyer S, Burk O, von Richter O 2000 Functional polymorphisms of the human multidrug – resistance gene: Multiple sequence variations and correlation of one allele with P – glycoprotein expressions activity in vivoProc Natl Acad Sci USA9773473347810.1073/pnas.050585397

3 

De Oliveire Almeida VC, Ribeiro DD, Gomes KB, Godard AL 2014 Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 genes and the therapeutic warfarin dose in Brazilian patients with thrombosis: a prospective cohort study Mol Diagn Ther 18 6 675 683 10.1007/s40291-014-0121-4