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Research ArticleArticle

Identification of Valproic Acid Glucuronide Hydrolase As a Key Enzyme for the Interaction of Valproic Acid with Carbapenem Antibiotics

Eiko Suzuki, Naotoshi Yamamura, Yuji Ogura, Daisuke Nakai, Kazuishi Kubota, Nobuhiro Kobayashi, Shin-ichi Miura and Osamu Okazaki
Drug Metabolism and Disposition September 2010, 38 (9) 1538-1544; DOI: https://doi.org/10.1124/dmd.110.032938
Eiko Suzuki
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Naotoshi Yamamura
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Yuji Ogura
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Daisuke Nakai
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Kazuishi Kubota
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Nobuhiro Kobayashi
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Shin-ichi Miura
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Osamu Okazaki
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Abstract

Plasma levels of valproic acid (VPA) are decreased by concomitant use with carbapenem antibiotics, such as panipenem (PAPM). One of the plausible mechanisms of this interaction is the inhibition of VPA glucuronide (VPA-G) hydrolysis by carbapenems in the liver. To elucidate this interaction mechanism, we purified VPA-G hydrolase from human liver cytosol, in which the hydrolytic activity was mainly located. After chromatographic purification, the VPA-G hydrolase was identified as acylpeptide hydrolase (APEH). APEH-depleted cytosol, prepared by an immunodepletion method, completely lacked the hydrolytic activity. These results demonstrate that APEH is a single enzyme involved in PAPM-sensitive VPA-G hydrolysis in cytosol. In addition, the hydrolytic activity of recombinant human APEH was inhibited by PAPM and the inhibition profile by typical esterase inhibitors (diisopropyl fluorophosphate, 5,5′-dithiobis(2-nitrobenzoic acid), p-chloromercuribenzoic acid, and d-saccharic acid 1,4-lactone) was similar to that of human liver cytosol. Cytosolic VPA-G hydrolase activity was slightly inhibited by cholinesterase and carboxylesterase inhibitors. β-Glucuronidase activity remained in APEH-depleted cytosol, whereas VPA-G hydrolase activity was completely abolished. Thus, either cholinesterase, carboxylesterase, or β-glucuronidase in cytosol would not be involved in VPA-G hydrolysis. Taken together, APEH plays a major role in the PAPM-sensitive VPA-G hydrolysis in the liver. These findings suggest that APEH could be a key enzyme for the drug interaction of VPA with carbapenems via VPA-G hydrolysis.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032938.

  • ABBREVIATIONS:

    VPA
    valproic acid
    VPA-G
    VPA glucuronide
    PAPM
    panipenem
    DRPM
    doripenem
    DFP
    diisopropyl fluorophosphate
    pNPG
    p-nitrophenyl β-glucuronide
    BNPP
    bis-p-nitrophenyl phosphate
    DTNB
    5,5′-dithiobis(2-nitrobenzoic acid)
    PCMB
    p-chloromercuribenzoic acid sodium salt
    AANA
    acetyl-alanine p-nitroanilide
    APEH
    acylpeptide hydrolase
    IS
    internal standard
    LC
    liquid chromatography
    LDH
    lactate dehydrogenase
    PAGE
    polyacrylamide gel electrophoresis
    MS/MS
    tandem mass spectrometry.

  • Received February 23, 2010.
  • Accepted June 15, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (9)
Drug Metabolism and Disposition
Vol. 38, Issue 9
1 Sep 2010
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Research ArticleArticle

Identification of Valproic Acid Glucuronide Hydrolase As a Key Enzyme for the Interaction of Valproic Acid with Carbapenem Antibiotics

Eiko Suzuki, Naotoshi Yamamura, Yuji Ogura, Daisuke Nakai, Kazuishi Kubota, Nobuhiro Kobayashi, Shin-ichi Miura and Osamu Okazaki
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1538-1544; DOI: https://doi.org/10.1124/dmd.110.032938

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Research ArticleArticle

Identification of Valproic Acid Glucuronide Hydrolase As a Key Enzyme for the Interaction of Valproic Acid with Carbapenem Antibiotics

Eiko Suzuki, Naotoshi Yamamura, Yuji Ogura, Daisuke Nakai, Kazuishi Kubota, Nobuhiro Kobayashi, Shin-ichi Miura and Osamu Okazaki
Drug Metabolism and Disposition September 1, 2010, 38 (9) 1538-1544; DOI: https://doi.org/10.1124/dmd.110.032938
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