In Vitro and In Vivo P-Glycoprotein Transport Characteristics of Rivaroxaban

Abstract

Rivaroxaban, an oral, direct factor Xa inhibitor, has a dual mode of elimination in humans, with two-thirds metabolized by the liver and one-third renally excreted unchanged. P-glycoprotein (P-gp) is known to be involved in the absorption, distribution, and excretion of drugs. To investigate whether rivaroxaban is a substrate of P-gp, the bidirectional flux of rivaroxaban across Caco-2, wild-type, and P-gp-overexpressing LLC-PK1 cells was investigated. Furthermore, the inhibitory effect of rivaroxaban toward P-gp was determined. Rivaroxaban exhibited high permeability and polarized transport across Caco-2 cells. Rivaroxaban was shown to be a substrate for, but not an inhibitor of, P-gp. Of a set of potential P-gp inhibitors, ketoconazole and ritonavir, but not clarithromycin or erythromycin, inhibited Pgp-mediated transport of rivaroxaban, with half-maximal inhibitory concentration values in the range of therapeutic plasma concentrations. These findings are in line with observed area under the plasma concentration-time curve increases in clinical drug-drug interaction studies indicating a possible involvement of P-gp in the distribution and excretion of rivaroxaban. In vivo studies in wild-type and P-gp double-knockout mice demonstrated that the impact of P-gp alone on the pharmacokinetics of rivaroxaban is minor. However, in P-gp double-knockout mice, a slight increase in brain concentrations and decreased excretion into the gastrointestinal tract were observed compared with wild-type mice. These studies also demonstrated that brain penetration of rivaroxaban is fairly low. In addition to P-gp, a further transport protein might be involved in the secretion of rivaroxaban.

Rivaroxaban postmarketing risk of liver injury

“…Of further note, previous studies indicated that rivaroxaban is a shared substrate of the drug transport proteins MDR1 and BCRP, whereas anticoagulant vitamin K antagonists are no strong substrates of MDR1 [17][18][19]. MDR1 inhibitors and loss-of-function BCRP polymorphisms may therefore alter rivaroxaban pharmacokinetics, and further studies may explore the potential role of these factors for rivaroxaban-induced DILI.…”

Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

“…P-gp was assumed to be solely responsible for the net renal secretion of rivaroxaban. A reversible K i value derived from a study using a known P-gp substrate digoxin was used for erythromycin, despite a recent report of minimal impact on P-gp mediated rivaroxaban transport in vitro by erythromycin [10]. Further model verification is needed for erythromycin's inhibition mechanisms, including sensitivity/uncertainty analyses of inhibition parameters.…”

“…In addition, passive glomerular filtration and active secretion mediated by transporters (likely P-glycoprotein, P-gp and/or breast cancer resistance protein, [1,5,9]) contribute to rivaroxaban renal clearance (CL R ) at a ratio of 1:5 [1,5]. The clearance of rivaroxaban appears to decrease in the elderly [1, 5,10].…”

Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co‐medication interactions

“…Drugs that exhibit strong effects on these proteins therefore have the potential to influence the pharmacokinetics, and thus the safety and efficacy profile, of rivaroxaban 7, 8. Consequently, strong inhibitors of both CYP3A4 and P‐gp are not recommended for systemic concomitant use with rivaroxaban 9.…”