PT  - JOURNAL ARTICLE
AU  - C. Weinz
AU  - T. Schwarz
AU  - D. Kubitza
AU  - W. Mueck
AU  - D. Lang
TI  - Metabolism and Excretion of Rivaroxaban, an Oral, Direct Factor Xa Inhibitor, in Rats, Dogs, and Humans
AID  - 10.1124/dmd.108.025569
DP  - 2009 May 01
TA  - Drug Metabolism and Disposition
PG  - 1056--1064
VI  - 37
IP  - 5
4099  - http://dmd.aspetjournals.org/content/37/5/1056.short
4100  - http://dmd.aspetjournals.org/content/37/5/1056.full
SO  - Drug Metab Dispos2009 May 01; 37
AB  - Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [14C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/intravenously) and dogs (orally), respectively. A single oral dose of [14C]rivaroxaban (10 mg) was administered to healthy human males (n = 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and ≥92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans. The American Society for Pharmacology and Experimental Therapeutics