Abstract
Side effects are the most common iatrogenic cause of damage to the patient. Drug and food interactions are the most prominent part of this phenomenon.
The greatest risk of severe interactions can be encountered with drugs influencing essential processes that also have narrow therapeutic window. Those are the characteristics of anticoagulants.
Thrombotic complications are present with their low action, bleeding when their action is high. This article reviews pharmacogenetic influences and drug interactions of direct oral anticoagulants (DOAC).
Regarding drug interactions based on pharmacogenetic effect, drugs increasing antithrombotic effect (i.e., with other antithrombotics) and drugs damaging the gastrointestinal mucosa (i.e., especially non-steroidal anti-inflammatory drugs) play the most important role. Generally, these types of interactions are known.
However, interactions influencing the fate of DOAC in the organism, i.e., pharmacokinetic interactions, are unexpected and often underrated. Increasing the concentration or exposition by a few tens of percents translates into an approximately the same increase in the risk of bleeding, as evidenced by large registration studies (RELY and ENGAGE) where two doses were used and population pharmacokinetics was observed.
Similarly, lowering the concentration or exposition decreases the antithrombotic effect. A relationship between the dose and the effect and safety exists.
The absorption of dabigatran etexilate is actively limited by the elimination P glycoprotein pump (P-gp). Moreover, absorption is possible only in an acidic environment.
In cardiology, the application of most widely used P-gp inhibitors - verapamil or amiodarone - increases the exposition to dabigatran by 60-70%. By contrast, co-medication with proton pump inhibitors (PPI) lowers the concentration of dabigatran by half.
Drug interactions with P-gp (or CYP3A4) can be encountered in all xabans; their importance is comparable to those of dabigatran. On the other hand, the absorption of xabans is not limited by PPI.
Similarly, P-gp inductors lower the exposition to all DOAC, dabigatran and xabans. Drug interaction with respect to moderate P-gp inhibitors (or CYP3A4) may reach significance when co-interacting with another factor modifying the exposition, especially with the decrease in renal function, body mass decrease, when more inhibitors are in action at once or with the influence of pharmacogenetic differences.