RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP dmd.114.058420 DO 10.1124/dmd.114.058420 A1 Donna Mamaril-Fishman A1 John Zhu A1 Min Lin A1 Clive Felgate A1 Lori Jones A1 Patrick Stump A1 Esaie Pierre A1 Chester Bowen A1 Odin Naderer A1 Etienne Dumont A1 Parul Patel A1 Peter D Gorycki A1 Bo Wen A1 Liangfu Chen A1 Yanli Deng YR 2014 UL http://dmd.aspetjournals.org/content/early/2014/05/28/dmd.114.058420.abstract AB 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.