Document Detail


Valproate metabolism during hepatotoxicity associated with the drug.
MedLine Citation:
PMID:  2290919     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Plasma concentrations of valproate and certain of its metabolites and their patterns of excretion in urine are described in three adults who developed hepatotoxicity during treatment of epilepsy with sodium valproate. One patient also developed a degree of reversible renal insufficiency, whilst another may have had associated infectious mononucleosis. All three cases showed evidence of impaired mitochondrial beta-oxidation of valproate. In one the impairment was at the stage catalysed by fatty acyl-CoA dehydrogenase, in another at the stage catalysed by 3-hydroxyacyl-CoA dehydrogenase and in the third at the stage catalysed by enoyl-CoA hydratase and possibly also at the next stage catalysed by 3-hydroxyacyl-CoA dehydrogenase. The impaired beta-oxidation meant that valproate metabolism was diverted into various alternative pathways. Plasma concentrations of the suspected hepatotoxic metabolite 4-en-valproate were normal for the valproate-treated population in all cases. By analogy with certain spontaneous and acquired human disorders of branched chain amino acid metabolism, it is suggested that valproate-associated hepatotoxicity may represent the consequences of a valproate overload on a limited mitochondrial beta-oxidation capacity, causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.
Authors:
M J Eadie; G E McKinnon; P R Dunstan; D MacLaughlin; R G Dickinson
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Publication Detail:
Type:  Case Reports; Journal Article    
Journal Detail:
Title:  The Quarterly journal of medicine     Volume:  77     ISSN:  0033-5622     ISO Abbreviation:  Q. J. Med.     Publication Date:  1990 Dec 
Date Detail:
Created Date:  1991-04-03     Completed Date:  1991-04-03     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0401027     Medline TA:  Q J Med     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1229-40     Citation Subset:  IM    
Affiliation:
Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
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MeSH Terms
Descriptor/Qualifier:
Adult
Drug-Induced Liver Injury*
Female
Half-Life
Humans
Liver Diseases / metabolism
Male
Middle Aged
Valproic Acid / adverse effects*,  blood,  metabolism,  urine
Chemical
Reg. No./Substance:
99-66-1/Valproic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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