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Research ArticleArticle

PROTEIN COVALENT BINDING OF MAXIPOST THROUGH A CYTOCHROME P450-MEDIATED ORTHO-QUINONE METHIDE INTERMEDIATE IN RATS

Donglu Zhang, Marc Ogan, Richard Gedamke, Vikram Roongta, Renke Dai, Mingshe Zhu, J. Kent Rinehart, Lewis Klunk and James Mitroka
Drug Metabolism and Disposition July 2003, 31 (7) 837-845; DOI: https://doi.org/10.1124/dmd.31.7.837
Donglu Zhang
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Marc Ogan
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Richard Gedamke
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Vikram Roongta
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Renke Dai
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Mingshe Zhu
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J. Kent Rinehart
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Lewis Klunk
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James Mitroka
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Abstract

(3S)-(+)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one) (MaxiPost, BMS-204352) is a potent and specific opener for maxi-K channels and has potential to prevent and treat ischemic stroke. Following single intravenous doses of [14C]BMS-204352 to rats, only 10 to 12% of radioactivity was extractable from plasma with organic solvents. The unextractable radioactivity remained associated with the proteins (mostly albumin) after SDS-polyacrylamide gel eletrophoresis or dialysis. Following acid hydrolysis in 6 M HCl for 24 h at 110°C from plasma proteins collected from nine rats dosed with [14C]BMS-204352, one major radioactive product was isolated and identified as a lysine-adduct of des-fluoro des-O-methyl BMS-204352 by liquid chromatography/mass spectrometry and NMR analyses as well as by comparison with the synthetic analog, lysine-adduct of des-fluoro BMS-204352 (BMS-349821). The covalent binding of BMS-204352 results from the displacement of the ring-fluorine atom of des-O-methyl BMS-204352 with the ϵ-amino group of a lysine residue. Microsomal incubations of [14C]BMS-204352 resulted in low levels of covalent binding of radioactivity to proteins. This in vitro covalent binding required cytochrome P450-reductase cofactor NADPH and was attenuated by glutathione. P4503A inhibitors ketoconazole and troleadomycin selectively prevented the covalent binding in vitro. Based on these observations, a two-step bioactivation process for the protein covalent binding of BMS-204352 was postulated: 1) P4503A-mediated O-demethylation leading to spontaneous release of HF and the formation of an ortho-quinone methide reactive metabolite and 2) nucleophilic addition of the ϵ-amino group of protein lysine residue(s) in protein to form des-fluoro des-O-methyl BMS-204352 lysine adduct.

Footnotes

  • ↵1 Abbreviations used are: BMS-204352, (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); HPLC, high performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; TLC, thin-layer chromatography; Boc, 1,1-(dimethylethoxy)carbonyl; DMSO, dimethyl sulfoxide; GSH, glutathione; P450, cytochrome P450.

    • Received December 16, 2002.
    • Accepted March 20, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (7)
Drug Metabolism and Disposition
Vol. 31, Issue 7
1 Jul 2003
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Research ArticleArticle

PROTEIN COVALENT BINDING OF MAXIPOST THROUGH A CYTOCHROME P450-MEDIATED ORTHO-QUINONE METHIDE INTERMEDIATE IN RATS

Donglu Zhang, Marc Ogan, Richard Gedamke, Vikram Roongta, Renke Dai, Mingshe Zhu, J. Kent Rinehart, Lewis Klunk and James Mitroka
Drug Metabolism and Disposition July 1, 2003, 31 (7) 837-845; DOI: https://doi.org/10.1124/dmd.31.7.837

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Research ArticleArticle

PROTEIN COVALENT BINDING OF MAXIPOST THROUGH A CYTOCHROME P450-MEDIATED ORTHO-QUINONE METHIDE INTERMEDIATE IN RATS

Donglu Zhang, Marc Ogan, Richard Gedamke, Vikram Roongta, Renke Dai, Mingshe Zhu, J. Kent Rinehart, Lewis Klunk and James Mitroka
Drug Metabolism and Disposition July 1, 2003, 31 (7) 837-845; DOI: https://doi.org/10.1124/dmd.31.7.837
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