title: Investigation of metabolism and disposition of GSK1322322, a peptidase deformylase inhibitor, in healthy humans using the entero-test for biliary sampling.
abstract: 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 [(14)C]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 [(14)C]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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Donna
authors.initials: D
authors.lastname: Mamaril-Fishman
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: John
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Clive
authors.initials: C
authors.lastname: Felgate
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Lori
authors.initials: L
authors.lastname: Jones
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Stump
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Esaie
authors.initials: E
authors.lastname: Pierre
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Chester
authors.initials: C
authors.lastname: Bowen
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Odin
authors.initials: O
authors.lastname: Naderer
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Etienne
authors.initials: E
authors.lastname: Dumont
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Parul
authors.initials: P
authors.lastname: Patel
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gorycki
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.).
authors.forename: Liangfu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania (D.M.F., M.L., E.P., C.B., P.D.G., B.W., L.C., Y.D.) and Ware, United Kingdom (C.F.); Department of Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, Pennsylvania (J.Z.); Department of Projects Clinical Pharmacology and Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina (L.J., P.S., O.N., P.P.) and Collegeville, Pennsylvania (E.D.) yanli.2.deng@gsk.com.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Deng
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001646:Bile / Q000378:metabolism*; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism* / Q000652:urine; D018592:Cross-Over Studies; D005243:Feces / Q000737:chemistry; D041981:Gastrointestinal Tract / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D010447:Peptide Hydrolases; D011480:Protease Inhibitors / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C583947:GSK1322322; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D010447:Peptide Hydrolases