The effect of aspirin on valproic acid metabolism

Abstract

Urinary valproic acid (VPA) and VPA metabolite profiles were determined before (day 1) and after (day 2) the administration of antipyretic doses of acetylsalicylic acid (ASA) to seven subjects with steady-state levels of VPA. Of the 13 metabolites assayed by GC/MS, levels of (E)-2-ene VPA and 3-keto VPA were significantly decreased on day 2, whereas those of the VPA conjugates (glucuronide) and 4-ene VPA were significantly increased. The beta-oxidation pathway consisting of (E)-2-ene VPA, 3-OH VPA, and 3-keto VPA was decreased from 24.5% +/- 10.3% of total metabolites excreted on day 1 to 8.3% +/- 4.2% on day 2, a decrease of 66% (P less than 0.05). VPA glucuronide content increased from 50.5% +/- 12.6% on day 1 to 65.5% +/- 14% of total excreted on day 2, an increase of 30% (P less than 0.05). The day 2/day 1 ratios of VPA glucuronide correlated significantly with the day 2/day 1 ratios of VPA mean free fraction (r = 0.9424; P = 0.005) in six of the seven subjects. Inhibition of VPA beta-oxidation by salicylate was sufficient to counterbalance the increased elimination of VPA as its conjugates and explains why total clearance of VPA after salicylate remains unchanged even though the free fraction of VPA is increased. Metabolic profiles indicate that salicylate likely inhibits VPA beta-oxidation by reducing valproyl-coenzyme A formation.

Urinary excretion of valproate metabolites in children and adolescents

“…The clearance of VPA, adjusted for weight, has been observed to decrease with age from childhood to adulthood [2][3][4]. The proportion of VPA excreted as oxidative metabolites appears to be increased in children relative to adults [1,5]. This may represent a true association between age and differential maturation of enzyme pathways or it may be the result of confounding due to autoinduction, co-medication with enzyme inducing or inhibiting medications, or dose related effects that may be unevenly distributed between age groups [6].…”

The effect of carbamazepine on valproic acid disposition in adult volunteers.

“…Lower serum VPA concentrations, despite higher VPA doses, have been observed in both adult (Reunanen et al, 1980) and paediatric patients (Abbott et al, 1986a) and clearance (CL) increased when VPA was coadministered with CBZ in adult epileptic patients (Hoffman et al, 1981).…”

Michael Reaction of Nitroalkanes with β‐Nitroacrylates under a Solid Promoter: Advanced Regio‐ and Diastereoselective Synthesis of Nitro‐Functionalized α,β‐Unsaturated Esters and 1,3‐Butadiene‐2‐carboxylates

“…[26,27] Metabolism of VPA occurs mainly in the liver and several complex metabolic pathways have been presented and of great interest are a series of diunsaturated metabolites. [28][29][30] However one of these, the compound 8a, is the most frequently found in patient serum and urine samples [31] and it possesses anticonvulsant activity in mice. [32,33] In order to undertake metabolic and pharmacokinetic studies of 8a, methods of syntheses that would yield significant quantities of this diene, were required.…”