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Research ArticleArticle

Involvement of Liver Carboxylesterases in the In Vitro Metabolism of Lidocaine

Stefan E. H. Alexson, Margareta Diczfalusy, Magnus Halldin and Stellan Swedmark
Drug Metabolism and Disposition June 2002, 30 (6) 643-647; DOI: https://doi.org/10.1124/dmd.30.6.643
Stefan E. H. Alexson
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Margareta Diczfalusy
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Magnus Halldin
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Stellan Swedmark
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Abstract

Although lidocaine has been used clinically for more than half a century, the metabolism has still not been fully elucidated. In the present study we have addressed the involvement of hydroxylations, deethylations, and ester hydrolysis in the metabolism of lidocaine to 2,6-xylidine. Using microsomes isolated from male rat liver, we found that lidocaine is mainly metabolized by deethylation toN-(N-ethylglycyl)-2,6-xylidine, andN-(N-ethylglycyl)-2,6-xylidine is mainly metabolized to N-glycyl-2,6-xylidine, also by deethylation. However, 2,6-xylidine can be formed both from lidocaine and N-(N-ethylglycyl)-2,6-xylidine, but not from N-glycyl-2,6-xylidine, in an NADPH-independent reaction, suggesting that the amido bond in these compounds can be directly hydrolyzed by esterases. To test this hypothesis, we incubated lidocaine,N-(N-ethylglycyl)-2,6-xylidine, andN-glycyl-2,6-xylidine with purified liver carboxylesterases. Rat liver microsomal carboxylesterase ES-10, but not carboxylesterase ES-4, hydrolyzed lidocaine andN-(N-ethylglycyl)-2,6-xylidine to 2,6-xylidine, identifying this esterase as a candidate enzyme in the metabolism of lidocaine.

Footnotes

  • Abbreviations used are::
    LIDO
    lidocaine
    3-OH-MEGX
    3-hydroxy-N-(N-ethylglycyl)-2,6-xylidine
    MEGX
    N-(N-ethylglycyl)-2,6-xylidine
    GX
    N-glycyl-2,6-xylidine
    3-OH-GX
    3-OH-N-glycyl-2,6-xylidine
    3-OH-LIDO
    3-OH-lidocaine
    Me-OH-LIDO
    methylhydroxylidocaine
    4-OH-XYL
    4-hydroxy-2,6-xylidine
    XYL
    2,6-xylidine
    BNPP
    bis-(nitrophenyl) phosphate
    P450
    cytochrome P450
    S-D
    Sprague-Dawley
    HPLC
    high-performance liquid chromatography
    LC/MS
    liquid chromatography/mass spectrometry
    • Received December 5, 2001.
    • Accepted February 22, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (6)
Drug Metabolism and Disposition
Vol. 30, Issue 6
1 Jun 2002
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Research ArticleArticle

Involvement of Liver Carboxylesterases in the In Vitro Metabolism of Lidocaine

Stefan E. H. Alexson, Margareta Diczfalusy, Magnus Halldin and Stellan Swedmark
Drug Metabolism and Disposition June 1, 2002, 30 (6) 643-647; DOI: https://doi.org/10.1124/dmd.30.6.643

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Research ArticleArticle

Involvement of Liver Carboxylesterases in the In Vitro Metabolism of Lidocaine

Stefan E. H. Alexson, Margareta Diczfalusy, Magnus Halldin and Stellan Swedmark
Drug Metabolism and Disposition June 1, 2002, 30 (6) 643-647; DOI: https://doi.org/10.1124/dmd.30.6.643
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