Chronic valproic acid intoxication in epileptology: diagnosis and treatment

Шнайдер, Н. А.; Дмитренко, Д. В.

doi:10.14412/2074-2711-2016-2-94-99

Cited by 7 publications

(12 citation statements)

References 13 publications

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“…The genome is consistent with various cell and tissue types in humans, although epigenomics and the regulation of genomic expression are highly dependent on cells and tissues, and since pharmacometabolomics is an “-omic” type of data that appears to be most closely associated with clinical phenotypes [ 128 , 132 ], the integration of pharmacogenomics and pharmacometabolomics may be particularly useful in achieving an optimal balance between the efficacy and safety of VPA. The use of genomic methods, such as genome-wide association studies, has been very successful [ 132 ], especially in situations where the phenotype of VPA drug metabolism in the liver in a particular patient is clearly defined (for example, P-oxidation involving cytochrome P450 isoenzymes) [ 37 ]. However, the use of pharmacogenomic methods alone was less successful when applied to complex and less defined phenotypes (for example, the «P-oxidation + glucuronidation + acetylation») of VPA metabolism in patients with common and rare neurological diseases and mental disorders.…”

Section: Discussionmentioning

confidence: 99%

“…For example, non-functional SNVs of CYP2C9*2 and CYP2C9*3 are associated with decreased VPA metabolism, so patients who are homozygous for CYP2C9*2 or CYP2C9*3 or who are heterozygous (CYP2C9*2/*3) have a PM phenotype and show decreased P-oxidation of VPA in liver microsomes [ 69 ]. Patients with homozygous CYP2C9*2/*2 and CYP2C9*3/*3 genotype had reduced oxidative biotransformation of VPA in liver microsomes compared to subjects with compound heterozygous CYP2C9*2/*3 genotype and catalyzed the formation of toxic metabolites 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA [ 37 ]. Therefore, pharmacogenetic profiling of the CYP2C9 gene in patients with neurological diseases and psychiatric disorders may help optimize VPA dosage, and prevent ADRs and iatrogenic worsening of the disease.…”

Section: Pharmacometabolomics and Pharmacogenomics Of Valproic Acidmentioning

confidence: 99%

“…The intensity of these two processes may be sufficient to compensate for the damage associated with the formation of reactive toxic metabolites of VPA. However, when using high doses of VPA and/or chronic pharmacotherapy, protective mechanisms may fail, leading to the development of serious VPA-induced adverse drug reactions (ADRs) [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic and Toxic Effects of Valproic Acid Metabolites

et al. 2023

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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).

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacometabolomics and Pharmacogenomics Of Valproic Acidmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic and Toxic Effects of Valproic Acid Metabolites

et al. 2023

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“…VPA metabolism and genetic biomarkers associated with changes in VPA pharmacokinetics continue to be actively studied [3]. Three main pathways of VPA biotransformation are known: P-oxidation via cytochrome 450 isoenzymes (CYPs); glucuronidation via uridylglucuronyltransferase (UGT) isoenzymes; and acetylation in the tricarboxylic acid cycle (mitochondrial oxidation) (Figure 1) [1,4,5].…”

Section: Introductionmentioning

confidence: 99%

Ethnic Aspects of Valproic Acid P-Oxidation

Shnayder,

Grechkina,

Trefilova

et al. 2024

Biomedicines

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The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review demonstrated the variability in allelic frequencies of low-functioning and non-functional single nucleotide variants in genes encoding key isoenzymes of valproic acid β-oxidation in the liver across different ethnic/racial groups. The sensitivity and specificity of pharmacogenetic testing panels for predicting the rate of metabolism of valproic acid by P-oxidation can be increased by prioritizing the inclusion of the most common risk allele characteristic of a particular population (country).

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“…Около 10-20% ВК метаболизируется через систему цитохрома Р450 [5] с обра-зованием 4-ene-VPA и гидрокси-метаболитов [6]. Хотя ци-тохром-катализируемый метаболизм ВК количественно не-значителен в сравнении с другими путями ее метаболизма, он, тем не менее, весьма интересен из-за развития явлений непереносимости и интоксикации вследствие образования ненасыщенных жирных кислот, являющихся промежуточ-ными продуктами метаболизма ВК (4-ene-VPA, 4-OH-VPA и 5-OH-VPA), поскольку в последние годы убедительно по-казан их токсический эффект на организм человека [7,8]. Основным катализатором гидроксилирования и десатура-ции ВК до 4-ene-VPA является изофермент CYP2C9 и, в меньшей мере, изоферменты CYP2A6 и CYP2B6 [9].…”

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