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Research ArticleArticle

Identification and Characterization ofN-Acetylcysteine Conjugates of Valproic Acid in Humans and Animals

Sashi V. Gopaul, Kevin Farrell and Frank S. Abbott
Drug Metabolism and Disposition July 2000, 28 (7) 823-832;
Sashi V. Gopaul
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Kevin Farrell
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Frank S. Abbott
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Abstract

Reactive and hepatotoxic metabolites formed from the biotransformation of valproic acid (VPA) are normally detoxified by conjugating with GSH and followed by mercapturic acid metabolism to produce their respective N-acetylcysteine (NAC) conjugates. Hence, the levels of NAC conjugates of VPA in human urine are an indirect measure of exposure of the liver toward reactive metabolites of the anticonvulsant drug. We report here the synthesis, identification, and characterization of a second NAC conjugate of (E)-2-propyl-2,4-pentadienoic acid in the urine samples (n = 39) of humans on VPA therapy, namely, (E)-5-(N-acetylcystein-S-yl)-2-ene VPA by gas chromatography/mass spectrometry and liquid chromatography with tandem mass spectrometry. In this study, we were able to separate the diastereomers of (E)-5-(N-acetylcystein-S-yl)-3-ene VPA by HPLC. The NAC conjugate of 4,5-epoxy VPA, namely, 5-NAC-4-OH-VPA γ-lactone, previously identified in rats treated with 2-propyl-4-pentenoic acid (4-ene VPA), was not detected in any of the human urine samples studied. This suggests that in humans, the P-450 metabolism of 4-ene VPA to the reactive epoxide is not a significant pathway. The excretion of the NAC conjugate of (E)-2,4-diene VPA glucuronide in the urine of seven patients on VPA was also examined and was not detected. The limit of detection of 5-NAC-3-keto VPA and its decarboxylated product, 1-NAC-3-heptanone, was estimated at 25 ng (signal to noise ratio > 3). Neither 5-NAC-3-keto VPA nor 1-NAC-3-heptanone was detected in the urine of patients on VPA therapy or 4-ene VPA-treated guinea pigs, but 1-NAC-3-heptanone was detected in the urine of 4-ene VPA-treated rats.

Footnotes

  • Send reprint requests to: Frank Abbott, Ph.D., The University of British Columbia, Faculty of Pharmaceutical Sciences, 2146 East Mall, Vancouver, British Columbia, Canada V6T 1Z3. E-mail:fabbott{at}interchange.ubc.ca

  • ↵1 A preliminary account of these studies was presented at the 44th American Society for Mass Spectrometry conference, Seattle, Washington, 1996 and at the 7th International Society for the Study of Xenobiotics meeting, San Diego, California, 1996.

  • This work was supported by the Medical Research Council of Canada Research Grant MT-13744 and was part of the doctoral dissertation and postdoctoral fellowship of S.V. Gopaul (1998).

  • Abbreviations used are::
    VPA
    valproic acid (2-propylpentanoic acid)
    CoA
    coenzyme A
    4-ene VPA
    2-propyl-4-pentenoic acid
    2-ene VPA
    2-propyl-2-pentenoic acid
    3-ene VPA
    2-propyl-3-pentenoic acid
    (E)-2,4-diene VPA
    (E)-2-propyl-2,4-pentadienoic acid
    3-keto-4-ene VPA
    2-propyl-3-oxo-4-pentenoic acid
    4,5-diOH-VPA γ-lactone
    3-n-propyl-5-hydroxymethyltetrahydro-2-furanone
    NAC
    N-acetylcysteine
    PFB
    pentafluorobenzyl
    PFBBr
    pentafluorobenzyl bromide
    t-BDMS
    tert-butyldimethylsilyl
    TMS
    trimethylsilyl
    TFA
    trifluoroacetic acid
    GC
    gas chromatography
    MS
    mass spectrometry
    LC/MS/MS
    liquid chromatography with tandem mass spectrometry
    EI
    electron impact
    NICI
    negative ion chemical ionization. NAC I, (E)-5-NAC-3-ene VPA
    NAC II
    (E)-5-NAC-2-ene VPA
    NAC III
    5-NAC-4-OH-VPA γ- lactone
    NAC IVa
    5-NAC-3-keto VPA
    NAC IVb
    1-NAC-3-heptanone
    NAC V
    5-NAC-3-ene VPA glucuronide
    HP
    Hewlett-Packard
    SIM
    selected ion monitoring
    MRM
    multiple reaction monitoring
    ES+
    positive electrospray
    • Received August 24, 1999.
    • Accepted April 12, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (7)
Drug Metabolism and Disposition
Vol. 28, Issue 7
1 Jul 2000
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Research ArticleArticle

Identification and Characterization ofN-Acetylcysteine Conjugates of Valproic Acid in Humans and Animals

Sashi V. Gopaul, Kevin Farrell and Frank S. Abbott
Drug Metabolism and Disposition July 1, 2000, 28 (7) 823-832;

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Research ArticleArticle

Identification and Characterization ofN-Acetylcysteine Conjugates of Valproic Acid in Humans and Animals

Sashi V. Gopaul, Kevin Farrell and Frank S. Abbott
Drug Metabolism and Disposition July 1, 2000, 28 (7) 823-832;
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