Five Doubly Unsaturated Metabolites of Valproic Acid in Urine and Plasma of Patients on Valproic Acid Therapy1)

Summary: The urine and plasma of epileptic patients receiving therapeutic doses of valproic acid (2-propyl-pentanoic acid) was found to contain five doubly unsaturated metabolites of valproic acid, which were identi-fied äs their trimethylsilyl derivatives by GC/MS. A series of reference substances was synthesized but only two of them were identical with native metabolites: 2(2-propenyl)-4-pentenoic acid ( = 4.4'-diene) and E-2-propyl-2.4-pentadienoic acid (E-2.4-diene). The mass-spectra of the five native metabolites are given. Preli-minary quantitative data obtained from four groups of patients indicate increased formation of doubly unsatu-rated metabolites when valproic acid-induced side-effects are present, and in cases of fatal hepatic failure. The 4.4'-diene has hitherto been found only in fatal cases with hepatic injury. Quantitative data are presented äs % of the sum of valproic acid plus all its detected metabolites. Fünf zweifach ungesättigte Metabolite der Valproinsäure in Urin und Plasma von epileptischen Patienten unter Behandlung mit Valproinsäur