%0 Journal Article %A Donna Mamaril-Fishman %A John Zhu %A Min Lin %A Clive Felgate %A Lori Jones %A Patrick Stump %A Esaie Pierre %A Chester Bowen %A Odin Naderer %A Etienne Dumont %A Parul Patel %A Peter D. Gorycki %A Bo Wen %A Liangfu Chen %A Yanli Deng %T Investigation of Metabolism and Disposition of GSK1322322, a Peptidase Deformylase Inhibitor, in Healthy Humans Using the Entero-Test for Biliary Sampling %D 2014 %R 10.1124/dmd.114.058420 %J Drug Metabolism and Disposition %P 1314-1325 %V 42 %N 8 %X GSK1322322 (N-((R)-2-(cyclopentylmethyl)-3-(2-(5-fluoro-6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-2-methylpyrimidin-4-yl)hydrazinyl)-3-oxopropyl)-N-hydroxy-formamide) is an antibiotic in development by GlaxoSmithKline. In this study, we investigated the metabolism and disposition of [14C]GSK1322322 in healthy humans and demonstrated the utility of the Entero-Test in a human radiolabel study. We successfully collected bile from five men using this easy-to-use device after single i.v. (1000 mg) or oral administration (1200 mg in a solution) of [14C]GSK1322322. GSK1322322 had low plasma clearance (23.6 liters/hour) with a terminal elimination half-life of ∼4 hours after i.v. administration. After oral administration, GSK1322322 was readily and almost completely absorbed (time of maximal concentration of 0.5 hour; bioavailability 97%). GSK1322322 predominated in the systemic circulation (>64% of total plasma radioactivity). An O-glucuronide of GSK1322322 (M9) circulated at levels between 10% and 15% of plasma radioactivity and was pharmacologically inactive. Humans eliminated the radioactive dose in urine and feces at equal proportions after both i.v. and oral doses (∼45%–48% each). 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 underestimated. An unusual N-dehydroxylated metabolite (a secondary amide) of GSK1322322 was observed primarily in the feces and was most likely formed by gut microbes. %U https://dmd.aspetjournals.org/content/dmd/42/8/1314.full.pdf