Therapeutic and Toxic Effects of Valproic Acid Metabolites

Abstract

Valproic acid (VPA) and its salts are psychotropic drugs that are widely used in neurological diseases (epilepsy, neuropathic pain, migraine, etc.) and psychiatric disorders (schizophrenia, bipolar affective disorder, addiction diseases, etc.). In addition, the indications for the appointment of valproate have been expanding in recent years in connection with the study of new mechanisms of action of therapeutic and toxic metabolites of VPA in the human body. Thus, VPA is considered a component of disease-modifying therapy for multiple tumors, neurodegenerative diseases (Huntington’s disease, Parkinson’s disease, Duchenne progressive dystrophy, etc.), and human immunodeficiency syndrome. The metabolism of VPA is complex and continues to be studied. Known pathways of VPA metabolism include: β-oxidation in the tricarboxylic acid cycle (acetylation); oxidation with the participation of cytochrome P-450 isoenzymes (P-oxidation); and glucuronidation. The complex metabolism of VPA explains the diversity of its active and inactive metabolites, which have therapeutic, neutral, or toxic effects. It is known that some active metabolites of VPA may have a stronger clinical effect than VPA itself. These reasons explain the relevance of this narrative review, which summarizes the results of studies of blood (serum, plasma) and urinary metabolites of VPA from the standpoint of the pharmacogenomics and pharmacometabolomics. In addition, a new personalized approach to assessing the cumulative risk of developing VPA-induced adverse reactions is presented and ways for their correction are proposed depending on the patient’s pharmacogenetic profile and the level of therapeutic and toxic VPA metabolites in the human body fluids (blood, urine).

Energy metabolism disturbance in migraine: From a mitochondrial point of view

“…Known pathways of VPA metabolism is β-oxidation in the tricarboxylic acid cycle (acetylation). This could also prove that there is a correlation between migraine and the TCA ( Figure 3 ) ( Shnayder et al, 2023 ).…”

“…Known pathways of VPA metabolism is βoxidation in the tricarboxylic acid cycle (acetylation). This could also prove that there is a correlation between migraine and the TCA (Figure 3) (Shnayder et al, 2023). MDH, malate dehydrogenase; IDH2, Isocitrate dehydrogenase 2; α-KGDH, α-ketoglutarate dehydrogenase; IMM, inner mitochondrial membrane; ETC, electron transport chain; NNT,nicotinamide nucleotide transhydrogenase; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate.…”

YouTube as a source of information on preventing the use of valproic acid in women during pregnancy

“…Valproic acid is a very useful drug for epilepsy-like treatment. And with the study of new mechanisms of therapeutic and toxic metabolites of valproic acid in humans, the indications for valproic acid sodium have been expanding in recent years [ 36 ]. However, there is a significant teratogenic risk associated with the use of VPA during pregnancy, and adverse consequences are likely to occur if treatment regimens are not promptly adjusted according to physician recommendations.…”

Anti-Seizure Medications on Trial Again: Accused of Parkinson’s Disease!

“…12 Valproic acid has many mechanisms of action some beneficial and some deleterious including mitochondrial dysfunction, GABAergic modulation, histone deacytlase inhibition, and fatty acid metabolism. 13 It is possible that one of the mechanisms of action affects dopaminergic pathways and can lead to PD, although some animal models of PD have shown neuroprotective effects for valproic acid. 14 So what judgment should the jury pass on these drugs?…”