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Research ArticleArticle

Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic

Gary D. Bowers, David Tenero, Parul Patel, Phuong Huynh, James Sigafoos, Kathryn O’Mara, Graeme C. Young, Etienne Dumont, Elizabeth Cunningham, Milena Kurtinecz, Patrick Stump, J. J. Conde, John P. Chism, Melinda J. Reese, Yun Lan Yueh and John F. Tomayko
Drug Metabolism and Disposition May 2013, 41 (5) 1070-1081; DOI: https://doi.org/10.1124/dmd.112.050153
Gary D. Bowers
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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David Tenero
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Parul Patel
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Phuong Huynh
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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James Sigafoos
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Kathryn O’Mara
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Graeme C. Young
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Etienne Dumont
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Elizabeth Cunningham
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Milena Kurtinecz
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Patrick Stump
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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J. J. Conde
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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John P. Chism
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Melinda J. Reese
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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Yun Lan Yueh
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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John F. Tomayko
Department of Drug Metabolism and Pharmacokinetics (G.D.B., P.H., J.S., K.O., J.P.C., M.J.R., Y.L.Y.), and Infectious Diseases Therapeutic Area (P.P.), GlaxoSmithKline, Research Triangle Park, North Carolina; Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Ware, UK (G.C.Y.); Department of Clinical Pharmacology, Modeling and Simulation (D.T.), API Chemistry and Analysis (J.J.C.), and Projects, Clinical Platforms and Sciences (E.C., P.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Clinical Statistics (M.K.) and Infectious Diseases Therapeutic Area (E.D., J.F.T.), GlaxoSmithKline, Collegeville, Pennsylvania
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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.

Footnotes

    • Received November 16, 2012.
    • Accepted February 25, 2013.
  • dx.doi.org/10.1124/dmd.112.050153.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (5)
Drug Metabolism and Disposition
Vol. 41, Issue 5
1 May 2013
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Research ArticleArticle

Disposition and Metabolism of GSK2251052 in Humans

Gary D. Bowers, David Tenero, Parul Patel, Phuong Huynh, James Sigafoos, Kathryn O’Mara, Graeme C. Young, Etienne Dumont, Elizabeth Cunningham, Milena Kurtinecz, Patrick Stump, J. J. Conde, John P. Chism, Melinda J. Reese, Yun Lan Yueh and John F. Tomayko
Drug Metabolism and Disposition May 1, 2013, 41 (5) 1070-1081; DOI: https://doi.org/10.1124/dmd.112.050153

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Research ArticleArticle

Disposition and Metabolism of GSK2251052 in Humans

Gary D. Bowers, David Tenero, Parul Patel, Phuong Huynh, James Sigafoos, Kathryn O’Mara, Graeme C. Young, Etienne Dumont, Elizabeth Cunningham, Milena Kurtinecz, Patrick Stump, J. J. Conde, John P. Chism, Melinda J. Reese, Yun Lan Yueh and John F. Tomayko
Drug Metabolism and Disposition May 1, 2013, 41 (5) 1070-1081; DOI: https://doi.org/10.1124/dmd.112.050153
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