Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants

Abstract

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

“…The corresponding isolated compound 6 was obtained in good yield [80] (Scheme 2). (11)(12)(13)(14), (24)(25)(26), copper nanoparticles supported on ZnO (CuNPs/ZnO), Et3N, tetrahydrofuran (THF), 160 °C.…”

“…The synthesis of novel triazoles were prepared by the 1,3-dipolar cycloaddition between the N-propargyl amines (11)(12)(13)(14) and the organic azide (24)(25)(26) catalyzed by copper nanoparticles supported on ZnO in tetrahydrofuran as solvent, triethylamine as base at 160 • C under microwave irradiation (Scheme 7) [93].…”

“…The electronic chemical potential for propargyl precursors 11-14 shows a mean of −3.0471 eV, with a maximum of −2.889 eV for molecule 11 and a minimum of −3.169 for molecule 13. For the arylazide compounds (24)(25)(26), the mean is −4.4049 eV, with a maximum of −4.277 eV for molecule 24 and a minimum of −4.490 eV for molecule 26. This implies that the reaction between precursors 11-14 and 24-26 present a medium polar character, and the electron density flux will take place from the propargylated molecule to the arylazide [94].…”

“…Mortality associated to thrombin is very high, and the currently available prescription drugs to prevent thrombosis in cardiovascular patients include heparins and warfarin. Rivaroxaban and Apixaban are the recently approved orally active agents available for FXa inhibition, whereas Dabigatran inhibits the thrombin directly [25]. Warfarin is the vitamin K antagonist, which, if taken incorrectly, increases the chances of dangerous bleeding.…”

The Protective Effect of Dabigatran and Rivaroxaban on DNA Oxidative Changes in a Model of Vascular Endothelial Damage with Oxidized Cholesterol

“…Certain common cardiovascular diseases (CVDs), such as venous thromboembolism, stroke or systemic embolism in non-valvular atrial fibrillation, can be controlled or treated using non-vitamin-K oral anticoagulants (NOAC). One such NOAC is dabigatran: a reversible competitive inhibitor of 2 of 13 thrombin that specifically inhibits both free and clot-bound thrombin and thrombin-induced platelet activation [8]. Another is rivaroxaban: a direct factor Xa inhibitor [9].…”