Investigation of metabolism and disposition of GSK1322322, a peptidase deformylase inhibitor, in healthy humans using the entero-test for biliary sampling
| Autor: | Liangfu Chen, Etienne Dumont, Lori S. Jones, Yanli Deng, Odin J. Naderer, Patrick Stump, Chester L. Bowen, Parul Patel, John Zhu, Bo Wen, Clive Felgate, Esaie Pierre, Peter D. Gorycki, Min Lin, Donna Mamaril-Fishman |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Metabolic Clearance Rate Metabolite Glucuronidation Pharmaceutical Science Administration Oral Biological Availability Urine Pharmacology Hydroxamic Acids chemistry.chemical_compound Feces Oral administration Bile Humans Protease Inhibitors Gastrointestinal tract Cross-Over Studies Half-life Middle Aged Bridged Bicyclo Compounds Heterocyclic Bioavailability Gastrointestinal Tract chemistry Half-Life Peptide Hydrolases |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 42(8) |
| ISSN: | 1521-009X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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