RT Journal Article SR Electronic T1 In Vitro Metabolism of Rivaroxaban, an Oral, Direct Factor Xa Inhibitor, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1046 OP 1055 DO 10.1124/dmd.108.025551 VO 37 IS 5 A1 D. Lang A1 C. Freudenberger A1 C. Weinz YR 2009 UL http://dmd.aspetjournals.org/content/37/5/1046.abstract AB 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. [14C]Rivaroxaban was incubated with liver microsomes and hepatocytes of rats, dogs, and humans. The samples were analyzed by high-performance liquid chromatography-14C-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. The American Society for Pharmacology and Experimental Therapeutics