title: 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 P-gp-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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Bayer Schering Pharma AG, Wuppertal, Germany. markjean.gnoth@bayerhealthcare.com
authors.forename: Mark Jean
authors.initials: MJ
authors.lastname: Gnoth
authors.forename: Ulf
authors.initials: U
authors.lastname: Buetehorn
authors.forename: Uwe
authors.initials: U
authors.lastname: Muenster
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarz
authors.forename: Steffen
authors.initials: S
authors.lastname: Sandmann
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000378:metabolism* / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D000069552:Rivaroxaban; D013552:Swine; D013876:Thiophenes / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban