PT - JOURNAL ARTICLE AU - Donglu Zhang AU - Kan He AU - Nirmala Raghavan AU - Lifei Wang AU - James Mitroka AU - Brad D. Maxwell AU - Robert M. Knabb AU - Charles Frost AU - Alan Schuster AU - Feng Hao AU - Zheming Gu AU - W. Griffith Humphreys AU - Scott J. Grossman TI - Comparative Metabolism of <sup>14</sup>C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans AID - 10.1124/dmd.108.025981 DP - 2009 Aug 01 TA - Drug Metabolism and Disposition PG - 1738--1748 VI - 37 IP - 8 4099 - http://dmd.aspetjournals.org/content/37/8/1738.short 4100 - http://dmd.aspetjournals.org/content/37/8/1738.full SO - Drug Metab Dispos2009 Aug 01; 37 AB - The metabolism and disposition of [14C]apixaban, a potent, reversible, and direct inhibitor of coagulation factor Xa, were investigated in mice, rats, rabbits, dogs, and humans after a single oral administration and in incubations with hepatocytes. In plasma, the parent compound was the major circulating component in mice, rats, dogs, and humans. O-Demethyl apixaban sulfate (M1) represented approximately 25% of the parent area under the time curve in human plasma. This sulfate metabolite was present, but in lower amounts relative to the parent, in plasma from mice, rats, and dogs. Rabbits showed a plasma metabolite profile distinct from that of other species with apixaban as a minor component and M2 (O-demethyl apixaban) and M14 (O-demethyl apixaban glucuronide) as prominent components. The fecal route was a major elimination pathway, accounting for &gt;54% of the dose in animals and &gt;46% in humans. The urinary route accounted for &lt;15% of the dose in animals and 25 to 28% in humans. Apixaban was the major component in feces of every species and in urine of all species except rabbit. M1 and M2 were common prominent metabolites in urine and feces of all species as well as in bile of rats and humans. In vivo metabolite profiles showed quantitative differences between species and from in vitro metabolite profiles, but all human metabolites were found in animal species. After intravenous administration of [14C]apixaban to bile duct-cannulated rats, the significant portion (approximately 22%) of the dose was recovered as parent drug in the feces, suggesting direct excretion of the drug from gastrointestinal tracts of rats. Overall, apixaban was effectively eliminated via multiple elimination pathways in animals and humans, including oxidative metabolism, and direct renal and intestinal excretion.