Valproate metabolism during valproate-associated hepatotoxicity in a surviving adult patient.
The plasma profiles of valproate (VPA), its beta-oxidation metabolites E-2-en-VPA and 3-oxo-VPA and its terminal desaturation metabolite 4-en-VPA, have been measured in a patient receiving NaVPA 1000 mg twice per day from early in the course of serious hepatotoxicity and for 2 weeks after the drug was stopped. Concurrent profiles of liver, renal and haematological function parameters were available. Relative to concurrent plasma VPA concentrations, E-2-en-VPA concentrations were not different to those of the VPA-treated epileptic population at any stage of the illness, whereas 3-oxo-VPA concentrations relative to concurrent VPA concentrations were abnormally high early in the toxicity, abnormally low at its peak (3-5 days later), and comfortably within normal limits for the treated epileptic population late in the recovery phase (9-13 days from the onset). When measurable, plasma 4-en-VPA concentrations were not elevated. The elimination half-life of VPA during the recovery phase was 100 h, which is some 6-12 times greater than values reported for this parameter in normal patients. These data clearly define, in this patient, a link between idiosyncratic VPA-associated hepatotoxicity at its onset and peak and the later stages of VPA beta-oxidation. Whether the beta-oxidation abnormalities are causative or a consequence of an as yet undefined defect is unknown. In this patient, 4-en-VPA was unlikely to have been involved in the pathogenesis of the toxicity.
McLaughlin
D B
DB
Department of Medicine, Clinical Sciences Building, University of Queensland, Royal Brisbane Hospital, QLD 4029, Brisbane, Australia.
Eadie
M J
MJ
Parker-Scott
S L
SL
Addison
R S
RS
Henderson
R D
RD
Hooper
W D
WD
Dickinson
R G
RG
D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000150:complications / Q000188:drug therapy; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D014057:Tomography, X-Ray Computed; D014635:Valproic Acid / Q000009:adverse effects* / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D014635:Valproic Acid