TY - JOUR T1 - Absorption, Distribution, Metabolism, and Excretion of the Novel Antibacterial Prodrug Tedizolid Phosphate JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1275 LP - 1284 DO - 10.1124/dmd.113.056697 VL - 42 IS - 8 AU - Voon Ong AU - Shawn Flanagan AU - Edward Fang AU - Howard J. Dreskin AU - Jeffrey B. Locke AU - Kenneth Bartizal AU - Philippe Prokocimer Y1 - 2014/08/01 UR - http://dmd.aspetjournals.org/content/42/8/1275.abstract N2 - Tedizolid phosphate is a novel antibacterial prodrug with potent activity against Gram-positive pathogens. In vitro and in vivo studies demonstrated that the prodrug is rapidly converted by nonspecific phosphatases to the biologically active moiety tedizolid. Single oral dose radiolabeled 14C-tedizolid phosphate kinetic studies in human subjects (100 µCi in 204 mg tedizolid phosphate free acid) confirmed a rapid time to maximum tedizolid concentration (Tmax, 1.28 hours), a long terminal half-life (10.6 hours), and a Cmax of 1.99 µg/ml. Metabolite analysis of plasma, fecal, and urine samples from rats, dogs, and humans confirmed that tedizolid is the only measurable metabolite in plasma after intravenous (in animals only) or oral administration and that tedizolid sulfate is the major metabolite excreted from the body. Excellent mass balance recovery was achieved and demonstrated that fecal excretion is the predominant (80–90%) route of elimination across species, primarily as tedizolid sulfate. Urine excretion accounted for the balance of drug elimination but contained a broader range of minor metabolites. Glucuronidation products were not detected. Similar results were observed in rats and dogs after both intravenous and oral administration. The tedizolid metabolites showed less potent antibacterial activity than tedizolid. The observations from these studies support once daily dosing of tedizolid phosphate and highlight important metabolism and excretion features that differentiate tedizolid phosphate from linezolid. ER -