Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice

The suitability of nanoparticles as a drug-carrier system for the antiepileptic valproic acid has been studied in mice. The aim of the study was to increase the brain-to-serum ratio of the drug to reduce dose-related side effects in the periphery. The influence of nanoparticles on the metabolism of valproic acid was also investigated. The serum kinetics and the brain tissue levels of valproic acid were not altered by administration with nanoparticles. However, the nanoparticles did inhibit the metabolic degradation of valproic acid via mitochondrial beta-oxidation but did not influence any other metabolic pathway. It can be concluded that nanoparticles loaded with valproic acid may help to reduce the toxic side effects of valproate therapy, not by reducing the therapeutically necessary dosage but by inhibition of formation of toxic metabolites. Using their ability to selectively block a pathway nanoparticles may serve as a tool to investigate the metabolic origin of metabolites and their contribution to therapeutic efficacy and side effects.