title: Associations between risk factors for valproate hepatotoxicity and altered valproate metabolism.
abstract: The effects of three risk factors for valproate (VPA) hepatotoxicity (i.e., young age, polypharmacy, and high VPA serum level) on the metabolism of VPA to its monounsaturated metabolites [2-en-VPA (2-en), 3-en-VPA (3-en) and 4-en-VPA (4-en)] were investigated in 106 patients treated with VPA (56 cases of monotherapy and 50 cases of polytherapy). In the monotherapy group, there was a significant negative correlation between age and 4-en/VPA ratio. In the same group, the 4-en/VPA ratio showed a significant positive correlation with serum VPA level, while 3-en/VPA and 2-en/VPA ratios showed significant negative correlations. In patients greater than 10 years, the 4-en/VPA ratio was significantly higher, while the 2-en/VPA ratio was significantly lower in the polytherapy group than in the monotherapy group. Our results indicate that all three risk factors clearly increase the metabolic conversion of VPA to 4-en, the most toxic VPA metabolite, and that polytherapy and high VPA serum level result in the inhibited beta-oxidative metabolism of VPA to 2-en. These altered VPA metabolic profiles are strikingly similar to the abnormal VPA metabolism previously reported in cases with fatal hepatic failure. Although VPA-induced fatal hepatotoxicity has been regarded as an idiosyncratic reaction, it is possible that these three factors enhance susceptibility to VPA hepatotoxicity by altering the metabolism of VPA.
authors.affiliation: Department of Neuropsychiatry, Hirosaki University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
authors.forename: K
authors.initials: K
authors.lastname: Otani
authors.forename: M
authors.initials: M
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Hirano
authors.forename: Y
authors.initials: Y
authors.lastname: Fukushima
authors.forename: H
authors.initials: H
authors.lastname: Muranaka
authors.forename: N
authors.initials: N
authors.lastname: Koide
authors.forename: M
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000367:Age Factors; D056486:Chemical and Drug Induced Liver Injury; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D012307:Risk Factors; D014635:Valproic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; C045022:2-propyl-4-pentenoic acid; C041285:valproic acid glucuronide; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid; C069738:2-propyl-2,4-pentadienoic acid