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Research ArticleArticle

METABOLISM, PHARMACOKINETICS, AND PROTEIN COVALENT BINDING OF RADIOLABELED MAXIPOST (BMS-204352) IN HUMANS

Donglu Zhang, Rajesh Krishna, Lifei Wang, Jianing Zeng, James Mitroka, Renke Dai, Narayanan Narasimhan, Richard A. Reeves, Nuggehally R. Srinivas and Lewis J. Klunk
Drug Metabolism and Disposition January 2005, 33 (1) 83-93; DOI: https://doi.org/10.1124/dmd.104.001412
Donglu Zhang
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Rajesh Krishna
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Lifei Wang
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Jianing Zeng
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James Mitroka
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Renke Dai
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Narayanan Narasimhan
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Richard A. Reeves
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Nuggehally R. Srinivas
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Lewis J. Klunk
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Abstract

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of 14C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg 14C-labeled BMS-204352 (50 μCi) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t1/2 of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of 14C-labeled BMS-204352 were observed in humans, dogs, and rats.

Footnotes

  • doi:10.1124/dmd.104.001412.

  • ABBREVIATIONS: BMS-204352, (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); AUC, area under the plasma concentration-time curve; LC/MS/MS, liquid chromatography/tandem mass spectrometry; Cmax, maximal drug plasma concentration; CLT, total body clearance; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; Tmax, time to reach the maximal drug concentration (at the Cmax); Vss, steady-state volume of distribution.

    • Received July 9, 2004.
    • Accepted October 19, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (1)
Drug Metabolism and Disposition
Vol. 33, Issue 1
1 Jan 2005
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Research ArticleArticle

METABOLISM, PHARMACOKINETICS, AND PROTEIN COVALENT BINDING OF RADIOLABELED MAXIPOST (BMS-204352) IN HUMANS

Donglu Zhang, Rajesh Krishna, Lifei Wang, Jianing Zeng, James Mitroka, Renke Dai, Narayanan Narasimhan, Richard A. Reeves, Nuggehally R. Srinivas and Lewis J. Klunk
Drug Metabolism and Disposition January 1, 2005, 33 (1) 83-93; DOI: https://doi.org/10.1124/dmd.104.001412

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Research ArticleArticle

METABOLISM, PHARMACOKINETICS, AND PROTEIN COVALENT BINDING OF RADIOLABELED MAXIPOST (BMS-204352) IN HUMANS

Donglu Zhang, Rajesh Krishna, Lifei Wang, Jianing Zeng, James Mitroka, Renke Dai, Narayanan Narasimhan, Richard A. Reeves, Nuggehally R. Srinivas and Lewis J. Klunk
Drug Metabolism and Disposition January 1, 2005, 33 (1) 83-93; DOI: https://doi.org/10.1124/dmd.104.001412
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