Valproate metabolism during hepatotoxicity associated with the drug

Eadie M.J., McKinnon G.E., Dunstan P.R., Maclaughlin D. and Dickinson R.G. (1990) Valproate metabolism during hepatotoxicity associated with the drug. QJM, 77 3: 1229-1240. doi:10.1093/qjmed/77.3.1229


Author Eadie M.J.
McKinnon G.E.
Dunstan P.R.
Maclaughlin D.
Dickinson R.G.
Title Valproate metabolism during hepatotoxicity associated with the drug
Journal name QJM   Check publisher's open access policy
ISSN 1460-2393
Publication date 1990-01-01
Sub-type Article (original research)
DOI 10.1093/qjmed/77.3.1229
Open Access Status Not yet assessed
Volume 77
Issue 3
Start page 1229
End page 1240
Total pages 12
Subject 2700 Medicine
Abstract 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 epliepsy 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 impairied mitochondrial β-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 β-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 β-oxidation capacity, causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Scopus Import - Archived
 
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