RT Journal Article
SR Electronic
T1 Investigation of Metabolism and Disposition of GSK1322322, a Peptidase Deformylase Inhibitor, in Healthy Humans Using the Entero-Test for Biliary Sampling
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1314
OP 1325
DO 10.1124/dmd.114.058420
VO 42
IS 8
A1 Mamaril-Fishman, Donna
A1 Zhu, John
A1 Lin, Min
A1 Felgate, Clive
A1 Jones, Lori
A1 Stump, Patrick
A1 Pierre, Esaie
A1 Bowen, Chester
A1 Naderer, Odin
A1 Dumont, Etienne
A1 Patel, Parul
A1 Gorycki, Peter D.
A1 Wen, Bo
A1 Chen, Liangfu
A1 Deng, Yanli
YR 2014
UL http://dmd.aspetjournals.org/content/42/8/1314.abstract
AB 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.