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In vitro assessment of P‐gp and BCRP transporter‐mediated drug–drug interactions of riociguat with direct oral anticoagulants
Author(s) -
Jacqueroux Elodie,
Mercier Clément,
MargelidonCozzolino Victor,
Hodin Sophie,
Bertoletti Laurent,
Delavenne Xavier
Publication year - 2020
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12504
Subject(s) - riociguat , pharmacology , abcg2 , rivaroxaban , apixaban , chemistry , drug interaction , pharmacokinetics , efflux , medicine , transporter , chronic thromboembolic pulmonary hypertension , atp binding cassette transporter , pulmonary hypertension , biochemistry , warfarin , gene , atrial fibrillation
As an alternative to vitamin K antagonists ( VKA s), direct oral anticoagulants ( DOAC s) are increasingly prescribed in combination with riociguat in the treatment of chronic thromboembolic pulmonary hypertension ( CTEPH ). Pharmacokinetics of riociguat and DOAC s 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 DOAC s using in vitro models. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK ‐ MDR 1 and MDCK ‐ BCRP models, in the absence and in the presence of increasing concentrations of riociguat (0.5–100 μ m ). Calculated efflux ratios were subsequently used to determine riociguat inhibition percentages and half maximal inhibitory concentration ( IC 50). P‐gp–mediated efflux of apixaban and rivaroxaban was inhibited by 8% and 21%, respectively, in the presence of 100 μ m riociguat. BCRP ‐mediated transport of apixaban and rivaroxaban was inhibited by 36% and 77%, respectively. IC 50s of riociguat on MDCK ‐ MDR 1 and MDCK ‐ BCRP models were higher than 100 μ m for apixaban and higher than 100 μ m and 46.5 μ m for rivaroxaban, respectively. This work showed an in vitro inhibition of BCRP ‐mediated DOAC s transport by riociguat. In vivo studies may be required to determine the clinical relevance of these transporter‐mediated interactions.

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