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Absence of both MDR 1 ( ABCB 1) and Breast Cancer Resistance Protein ( ABCG 2) Transporters Significantly Alters Rivaroxaban Disposition and Central Nervous System Entry
Author(s) -
Gong Inna Y.,
Mansell Sara E.,
Kim Richard B.
Publication year - 2013
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12005
Subject(s) - rivaroxaban , abcg2 , pharmacology , organic cation transport proteins , efflux , organic anion transporter 1 , medicine , transporter , chemistry , atp binding cassette transporter , biochemistry , warfarin , gene , atrial fibrillation
Rivaroxaban is a novel factor 10a inhibitor, where hepatic metabolism and renal clearance account for its overall disposition. Renal impairment is known to increase rivaroxaban‐associated bleeding risk in patients. As renal rivaroxaban clearance exceeds glomerular filtration rate, we suggested that active secretion by efflux transporters P‐glycoprotein ( MDR 1) and breast cancer resistance protein ( BCRP ) contributes to rivaroxaban clearance. The ability of MDR 1 and BCRP efflux transporters to mediate rivaroxaban transport in vitro was assessed in polarized cell monolayers. A significantly greater vectorial transport of rivaroxaban was observed in the basal to apical direction in C aco‐2 cells, which was attenuated in the presence of the selective inhibitors. After oral administration of rivaroxaban (2 mg/kg), plasma concentrations did not significantly differ between wild‐type and M dr1a def or B crp −/− mice (n = 6 per group). However, rivaroxaban clearance was significantly reduced in M dr1a/ M dr1b −/− / B crp −/− mice. Interestingly, rivaroxaban brain‐to‐plasma ratio did not differ in mice lacking only M dr1a or B crp, but more than two times higher in the M dr1a/ M dr1b −/− / B crp −/− mice. Rivaroxaban is a shared substrate of MDR 1 and BCRP . In vivo , MDR and BCRP function synergistically to modulate rivaroxaban disposition and appear to be particularly relevant to limiting its central nervous system entry. These data have important implications for safety and efficacy of anticoagulation therapy with rivaroxaban as many drugs in clinical use are known MDR 1 inhibitors and loss‐of‐function polymorphisms in BCRP are common.