RT Journal Article
SR Electronic
T1 Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1070
OP 1081
DO 10.1124/dmd.112.050153
VO 41
IS 5
A1 Gary D. Bowers
A1 David Tenero
A1 Parul Patel
A1 Phuong Huynh
A1 James Sigafoos
A1 Kathryn O’Mara
A1 Graeme C. Young
A1 Etienne Dumont
A1 Elizabeth Cunningham
A1 Milena Kurtinecz
A1 Patrick Stump
A1 J. J. Conde
A1 John P. Chism
A1 Melinda J. Reese
A1 Yun Lan Yueh
A1 John F. Tomayko
YR 2013
UL http://dmd.aspetjournals.org/content/41/5/1070.abstract
AB (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.