title: In vitro metabolism of rivaroxaban, an oral, direct factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans.
abstract: The in vitro metabolism of rivaroxaban, a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders, was investigated in several species, including humans. The objective of this study was to elucidate metabolite structures and identify the metabolic pathways to provide support for in vivo safety and clinical studies. [(14)C]Rivaroxaban was incubated with liver microsomes and hepatocytes of rats, dogs, and humans. The samples were analyzed by high-performance liquid chromatography-(14)C-tandem mass spectroscopy, to generate metabolite profiles and propose or confirm the structures of the metabolites formed. In vitro metabolite profiles showed no major differences between species. The main oxidative metabolic pathways identified for all species were hydroxylation at the morpholinone moiety (M-2, M-3, and M-8) and to a lesser extent at the oxazolidinone moiety (M-9). M-2 was the main metabolite in all microsomal incubations. M-1, a morpholinone ring-opened product formed by further oxidation of M-2, was the main metabolite in all hepatocyte incubations. Other pathways were amide hydrolysis at the morpholinone ring (M-7) and the chlorothiophene amide moiety (M-13 and M-15). In hepatocytes, M-13 was readily conjugated with glycine, leading to M-4. The metabolic fate of unlabeled M-15 was investigated separately. Incubations with human liver microsomes and hepatocytes showed that M-15 was first oxidized to the aldehyde intermediate M-16 and subsequently reduced to M-17 (alcohol) or oxidized to M-18 (carboxylic acid). No metabolism at the chlorothiophene moiety itself was found. Overall, rivaroxaban showed no species differences in metabolism, with different independent metabolic pathways and no formation of reactive metabolites.
authors.affiliation: Bayer HealthCare AG, Global Drug Discovery, DMPK-Drug Metabolism, Building 466, Aprather Weg 18a, D-42096 Wuppertal, Germany. dieter.lang@bayerhealthcare.com
authors.forename: D
authors.initials: D
authors.lastname: Lang
authors.forename: C
authors.initials: C
authors.lastname: Freudenberger
authors.forename: C
authors.initials: C
authors.lastname: Weinz
mesh_terms: D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D065427:Factor Xa Inhibitors; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D009025:Morpholines / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D000069552:Rivaroxaban; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000493:pharmacokinetics*
chemical_list: D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban