Trichostatin A TSA be mediated by p glycoprotein an intestinal drug transporter so potent p

be mediated by p glycoprotein an intestinal drug transporter so potent p Gp inhibitors may increase drug concentrations.32 Trichostatin A TSA The half life ranges between 5 hours and 9 hours in healthy subjects and between 11 hours and 13 hours in elderly subjects.33 36 Compared with apixaban and rivaroxaban, edoxaban has a lower bioavailability of around 50% and a half life of 9 11 hours in young healthy subjects with a combined elimination pathway: 35% is renally excreted and 62% is excreted via feces.37 39 Edoxaban is also a substrate of p Gp, so strong inhibitors could lead to a higher concentration of edoxaban.40 The metabolism in liver microsomes is mediated mainly by CYP3A4 related pathways.41 In contrast to these oral factor Xa inhibitors, dabigatran is an oral direct thrombin inhibitor, which binds to the active binding site of thrombin and inhibits its activation.
Dabigatran exhibits a pharmacological profile different from that of FXA inhibitors. Given as a prodrug, the substance is rapidly absorbed.42 However, dissolution and absorption require an acidic microenvironment, and therefore dabigatran etexilate capsules contain a core of tartaric acid to stabilize the variations in gastric pH. Despite this, submit your manuscript | www.dovepress.com Dovepress INO-1001 Dovepress 140 Werth et al Therapeutics and Clinical Risk Management 2012:8 oral bioavailability is low with values around 6%. Peak plasma concentrations of dabigatran are reached approximately 2 hours after oral administration. Half life in healthy volunteers is 12 17 hours but prolonged in elderly patients or patients with impaired renal function, because nearly 90% of dabigatran is renally excreted.
Dabigatran is not metabolized by CYP450 isoenzymes. Drug drug interactions of NOACs With apixaban, pharmacological interactions are seen with comedications of azol type antimycotics such as ketoconazol or HIV protease inhibitors such as ritonavir, which result in an increase of the area under the curve and the maximum concentration for apixaban, potentially increasing bleeding risks. Therefore, apixaban treatment is contraindicated in patients receiving these drugs. Similar interactions are seen with rivaroxaban and edoxaban.35 On the other hand, coadministration of rifampicin leads to a significantly lower area under the curve and thereby to a significantly lower efficacy of apixaban, rivaroxaban, or edoxaban, which needs to be considered because insufficient anticoagulant efficacy may result from this interaction.
In patients receiving dabigatran, concomitant treatment with strong p Gp inhibitors like amiodaron, verapamil, chinidin, Intrinsic coagulation activation Extrinsic coagulation activation Binding in prothrombinase complex Amplification by 1000 times Thrombin generation IIa inhibitors Factor X inhibitors F X FXa FVa Ca2 F IIa Clot formation F II FXa Figure 1 Simplified model of coagulation activation, clot formation, and mode of action of new oral anticoagulants. Notes: Intrinsic and extrinsic coagulation activation leads to activation of factor X, which is bound into the prothrombinase complex consisting of phospholipids, calcium, activated factor V, and FXa. Bound in this complex, a singe molecule of FXa can activate degredation of 1000 molecules of prothrombin to active thrombin, which ultimately induces clot formation. Factor Xa inhibitors inhibit both free and complex bound active factor Xa. On the other hand, direct thrombin inhibitors inactivate the thrombin generated by coagul