This study allowed identification of three different profiles of ABC carrier-mediated transport: predominantly P-gp-dependent transport (dabigatran), preferential BCRP-dependent transport (apixaban) and approximately equivalent P-gp and BCRP-mediated transport (edoxaban and rivaroxaban).

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Because of their lower bleeding risk and simplicity of use, direct oral anticoagulants (DOACs) could represent an interesting alternative to conventional anticoagulant treatment with vitamin K antagonists for patients with pulmonary arterial hypertension (PAH). P-glycoprotein (P-gp) plays a key role in DOAC pharmacokinetics. Type 5-phosphodiesterase inhibitors (PDE5is), 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 PDE5is and DOACs using in vitro methods. A cellular model of drug transport assay, using P-gp-overexpressing Madin-Darby canine kidney cells (transfected with the human P-gp gene), was used to determine the bidirectional permeabilities of two DOACs (rivaroxaban and apixaban) in the absence and presence of increasing concentrations (0.5-100 M) of three PDE5is (sildenafil, tadalafil, and vardenafil). Permeabilities and efflux ratios were calculated from DOAC concentrations, were measured with liquid chromatography coupled with mass spectrometry, and were subsequently used to determine the PDE5i percentage of inhibition and half maximal inhibitory concentration (IC ). Rivaroxaban efflux was inhibited by 99%, 66%, and 100% with 100 M sildenafil, tadalafil, and vardenafil, respectively. Similarly, apixaban efflux was inhibited by 97%, 74%, and 100%, respectively. The IC values of the three PDE5is were 8, 28, and 5 M for rivaroxaban and 23, 15, and 3M for apixaban, respectively. This study showed strong in vitro inhibition of DOAC efflux by PDE5is. In vivo studies are required to determine the clinical relevance of these interactions.

As an alternative to vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) are increasingly prescribed in combination with riociguat in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Pharmacokinetics of riociguat and DOACs are influenced by efflux transporters, such as P‐glycoprotein (P‐gp) and Breast Cancer Resistance Protein (BCRP). This work aimed to assess P‐gp and BCRP‐mediated drug–drug interactions of riociguat with DOACs using in vitro models. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK‐MDR1 and MDCK‐BCRP models, in the absence and in the presence of increasing concentrations of riociguat (0.5–100 μm). Calculated efflux ratios were subsequently used to determine riociguat inhibition percentages and half maximal inhibitory concentration (IC50). P‐gp–mediated efflux of apixaban and rivaroxaban was inhibited by 8% and 21%, respectively, in the presence of 100 μm riociguat. BCRP‐mediated transport of apixaban and rivaroxaban was inhibited by 36% and 77%, respectively. IC50s of riociguat on MDCK‐MDR1 and MDCK‐BCRP models were higher than 100 μm for apixaban and higher than 100 μm and 46.5 μm for rivaroxaban, respectively. This work showed an in vitro inhibition of BCRP‐mediated DOACs transport by riociguat. In vivo studies may be required to determine the clinical relevance of these transporter‐mediated interactions.

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