TY - JOUR T1 - Investigation of Metabolism and Disposition of GSK1322322, a PDF Inhibitor, in Healthy Humans Using Entero-Test® For Biliary Sampling JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.114.058420 SP - dmd.114.058420 AU - Donna Mamaril-Fishman AU - John Zhu AU - Min Lin AU - Clive Felgate AU - Lori Jones AU - Patrick Stump AU - Esaie Pierre AU - Chester Bowen AU - Odin Naderer AU - Etienne Dumont AU - Parul Patel AU - Peter D Gorycki AU - Bo Wen AU - Liangfu Chen AU - Yanli Deng Y1 - 2014/05/28 UR - http://dmd.aspetjournals.org/content/early/2014/05/28/dmd.114.058420.abstract N2 - GSK1322322 is an antibiotic in development by GlaxoSmithKline. In this study, we investigated metabolism and disposition of [14C]GSK1322322 in healthy humans, and demonstrated the utility of Entero-Test® in a human radiolabel study. We successfully collected bile in five men with this easy-to-use device following single intravenous (1000 mg) and oral administration (1200 mg in solution) of [14C]GSK1322322. GSK1322322 had low plasma clearance (23.6 L/h) with a terminal elimination half life of ~4 h following IV administration. Following oral administration, GSK1322322 was readily and almost completely absorbed (Tmax of 0.5 h; bioavailability of 97%). GSK1322322 predominated in systemic circulation (> 64% of total plasma radioactivity). An O-glucuronide of GSK1322322 (M9) circulated at levels between 10-15% of plasma radioactivity, and was pharmacologically inactive. Humans eliminated the radioactive dose in urine and feces at equal proportions after both IV and oral doses. Urine contained mostly unchanged GSK1322322, accounting for 30% of the dose. Bile contained mostly M9, indicating that glucuronidation was likely a major pathway in humans (up to 30% of total dose). In contrast, M9 was found in low amounts in feces, indicating its instability in the gastrointestinal tract. Therefore, without the Entero-test bile data, the contribution of glucuronidation would have been notably under-estimated. An unusual N-dehydroxylated metabolite (a secondary amide) of GSK1322322 was primarily observed in the feces, and most likely formed by gut microbes. ER -