Absence of both MDR1 (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Transporters Significantly Alters Rivaroxaban Disposition and Central Nervous System Entry

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 (MDR1) and breast cancer resistance protein (BCRP) contributes to rivaroxaban clearance. The ability of MDR1 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 Caco‐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 Mdr1a^def or Bcrp^?/? mice (n = 6 per group). However, rivaroxaban clearance was significantly reduced in Mdr1a/Mdr1b^?/?/Bcrp^?/? mice. Interestingly, rivaroxaban brain‐to‐plasma ratio did not differ in mice lacking only Mdr1a or Bcrp, but more than two times higher in the Mdr1a/Mdr1b^?/?/Bcrp^?/? mice. Rivaroxaban is a shared substrate of MDR1 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 MDR1 inhibitors and loss‐of‐function polymorphisms in BCRP are common.