Title page Metabolism and excretion of rivaroxaban -an oral, direct Factor Xa inhibitor -in rats, dogs and humans

Abstract

Words in Abstract: 246 Words in Introduction: 246 Words in Discussion: 977 Abbreviations: AUC, area under the concentration-time curve; AUC norm , AUC normalized to rivaroxaban dose and body weight ; AUC 0-tn , AUC from 0 to the terminal time point; BDC, bile duct-cannulated; C max , maximum plasma concentration; C max,norm , C max normalized to rivaroxaban dose and body weight; ESI, electrospray ionization; FXa, Factor Xa; HPLC, high-performance liquid chromatography; i.v., intravenous; LC, liquid chromatography; LOQ, limit of quantification; LSC, liquid scintillation counting; MS, mass spectrometry; PK, pharmacokinetic; p.o., per oral and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25% and 52%, and faecal 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 faeces. 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 faecal/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