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In vitro assessment of pharmacokinetic drug-drug interactions of direct oral anticoagulants: type 5-phosphodiesterase inhibitors are inhibitors of rivaroxaban and apixaban efflux by P-glycoprotein.

In vitro assessment of pharmacokinetic drug-drug interactions of direct oral anticoagulants: type 5-phosphodiesterase inhibitors are inhibitors of rivaroxaban and apixaban efflux by P-glycoprotein.
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Margelidon-Cozzolino V, Hodin S, Jacqueroux E, Delezay O, Bertoletti L, Delavenne X,


Margelidon-Cozzolino V, Hodin S, Jacqueroux E, Delezay O, Bertoletti L, Delavenne X, (click to view)

Margelidon-Cozzolino V, Hodin S, Jacqueroux E, Delezay O, Bertoletti L, Delavenne X,

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The Journal of pharmacology and experimental therapeutics 2018 03 23() pii jpet.117.245993
Abstract

Direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists in pulmonary arterial hypertension (PAH) patients because of lower bleeding risk and their simplicity of use. P-glycoprotein (P-gp) plays a key role in DOACs pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5i), a drug class commonly used in the treatment of PAH, have been shown to strongly inhibit P-gp. This work aimed to assess potential P-gp mediated-drug-drug interactions between PDE5i and DOACs using in vitro methods. A cellular model of drug transport assay, using P-gp overexpressing MDCK-mdr1 cell line, was used to determine bidirectional permeabilities of two DOACs, rivaroxaban and apixaban, in absence and in presence of increasing concentrations (0.5-100 µM) of three PDE5i (sildenafil, tadalafil, and vardenafil). Permeabilities and efflux ratios were calculated from DOAC concentrations, measured with Liquid Chromatography coupled with Mass Spectrometry and were subsequently used to determine PDE5i percentage of inhibition and IC50. Rivaroxaban efflux was inhibited by 99%, 66% and 100%, with 100 µM of sildenafil, tadalafil and vardenafil, respectively. Similarly, apixaban efflux was inhibited by 97%, 74%, 100%, respectively. Half maximal inhibitory concentration (IC50) of the three PDE5i were respectively 8, 28 and 5 µM for rivaroxaban, and 23, 15 and 3 µM for apixaban. This study showed a strong in vitro inhibition of DOACs efflux by PDE5i. In vivo studies are required to determine clinical relevance of these interactions.

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