title: Disposition and metabolism of GSK2251052 in humans: a novel boron-containing antibiotic.
abstract: (S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [¹⁴C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.
authors: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. gary.d.bowers@gsk.com
authors: Gary D
authors: GD
authors: Bowers
authors: David
authors: D
authors: Tenero
authors: Parul
authors: P
authors: Patel
authors: Phuong
authors: P
authors: Huynh
authors: James
authors: J
authors: Sigafoos
authors: Kathryn
authors: K
authors: O'Mara
authors: Graeme C
authors: GC
authors: Young
authors: Etienne
authors: E
authors: Dumont
authors: Elizabeth
authors: E
authors: Cunningham
authors: Milena
authors: M
authors: Kurtinecz
authors: Patrick
authors: P
authors: Stump
authors: J J
authors: JJ
authors: Conde
authors: John P
authors: JP
authors: Chism
authors: Melinda J
authors: MJ
authors: Reese
authors: Yun Lan
authors: YL
authors: Yueh
authors: John F
authors: JF
authors: Tomayko
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001895:Boron / Q000032:analysis*; D001896:Boron Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry
chemical_list: C583949:3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole; D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D001895:Boron