Investigation of the arcane inhibition of human organic anion transporter 3 by benzofuran antiarrhythmic agents
| Autor: | Heng Lin Tan, Sheng Yuan Chin, Lloyd Wei Tat Tang, Eric Chun Yong Chan |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Organic anion transporter 1
medicine.drug_class Amiodarone Pharmaceutical Science Organic Anion Transporters Sodium-Independent Pharmacology Cell Line Benzbromarone chemistry.chemical_compound Rivaroxaban Atrial Fibrillation medicine Humans Drug Interactions Pharmacology (medical) ATP Binding Cassette Transporter Subfamily B Member 1 Benzofuran Dronedarone Benzofurans biology Chemistry Anticoagulant Apical membrane HEK293 Cells biology.protein Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Drug Metabolism and Pharmacokinetics. 38:100390 |
| ISSN: | 1347-4367 |
| DOI: | 10.1016/j.dmpk.2021.100390 |
| Popis: | The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected Ki values of 0.042, 0.019, 0.028 and 0.0046 μM respectively. Protein binding effects and probe substrate dependency were accounted for in our assays. Static modelling predicted 1.29-, 1.01-, 1.29- and 1.16-fold increase in rivaroxaban exposure, culminating in a predicted 1.29-, 1.01-, 1.28- and 1.15-fold increase in major bleeding risk respectively, suggesting potential OAT3-mediated DDI between amiodarone and rivaroxaban. Future work involving physiologically-based pharmacokinetic modelling is crucial in holistically predicting the complex DDIs between the benzofuran antiarrhythmic agents and rivaroxaban. |
| Databáze: | OpenAIRE |
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