METABOLIC-FATE OF VALPROIC ACID IN THE RHESUS-MONKEY - FORMATION OF A TOXIC METABOLITE, 2-NORMAL-PROPYL-4-PENTENOIC ACID

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  • 1 July 1986
    • journal article
    • research article
    • Vol. 14  (4) , 443-453
Abstract
The metabolic fate of an iv bolus dose (13.5 mg kg-1) of valproic acid (VPA) was studied in adult male rhesus monkeys. Renal excretion proved to be the major route of elmination of the drug and a total of 17 metabolites, accounting collective for some 82% of the administered dose, were identified in urine by GC-MS techniques. Many of these metabolites were present largely in the form of glucuronide conjugates, as was VPA itself. The prinicipal pathways of VPA biotransformation were, in order of decreasing quantitative importance, ester glucuronide formation, .omega.-oxidation, .beta.-oxidation and (.omega.-1)-hydroxylation. In addition, three mono-unsaturated metabolites, identified as (E)-.DELTA.2-, (E)-.DELTA.3-, and .DELTA.4-VPA, were detected in both plasma and urine. Quantitative analysis of these unsaturated VPA metabolites indicated that the .DELTA.4 olefin, which is known to be a potent hepatotoxic agent, was the predominant isomer of the group.