Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8513982 | Journal of Pharmaceutical Sciences | 2017 | 46 Pages |
Abstract
This study aimed to investigate the interactions of 3 anticoagulants, rivaroxaban, apixaban, and dabigatran, with 5 human solute carrier transporters, hOAT1, hOAT3, hOCT2, hOATP1B1, and hOATP1B3. Apixaban inhibited hOAT3, hOATP1B1, and hOATP1B3, and rivaroxaban inhibited hOAT3 and hOATP1B3, with IC50 values of >20 and >5 μM, respectively. The effect of dabigatran was negligible or very weak, so significant drug interactions at therapeutic doses are unlikely. Specific uptake of rivaroxaban was observed only in human and mouse OAT3-expressing cells. The Km for mouse Oat3 (mOat3) was 1.01 ± 0.70 μM. A defect in mOat3 reduced the kidney-to-plasma concentration ratio of rivaroxaban by 38% in mice. Probenecid treatment also reduced the kidney-to-plasma concentration ratio of rivaroxaban in rats by 73%. Neither mOat3 defect nor probenecid administration in rats reduced the renal clearance of rivaroxaban. The uptake of rivaroxaban by monkey kidney slices was temperature dependent and inhibited by probenecid but not by tetraethylammonium. Taken together, organic anion transporters, mainly OAT3, may mediate basolateral uptake of rivaroxaban in kidneys. hOAT3 could be an additional factor that differentiates the potential drug-drug interactions of the 3 anticoagulants in the urinary excretion process in clinical settings.
Keywords
PAHEstrone 3-sulfateE217βGCCK8OATPP-gpBcrp1-methyl-4-phenylpyridiniumCholecystokinin-8SLCPBSLC-MS/MSMPP+p-aminohippuric acidP-glycoproteinsolute transportersrenal transportOctTetraethylammoniumDrug interactionsOatsolute carrierorganic cation transporterorganic anion transporterPharmacokinetics/pharmacodynamicsPhosphate-buffered salinebreast cancer resistance proteinorganic anion-transporting polypeptideTEAliquid chromatography–tandem mass spectrometry
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Authors
Yuri Tsuruya, Takeo Nakanishi, Hisakazu Komori, Xinying Wang, Naoki Ishiguro, Tomoko Kito, Kouji Ikukawa, Wataru Kishimoto, Sumito Ito, Olaf Schaefer, Thomas Ebner, Norio Yamamura, Hiroyuki Kusuhara, Ikumi Tamai,