Analysis of variability of concentrations of valproic acid (VPA) and its selected metabolites in the blood serum of patients treated with VPA and patients hospitalized because of VPA poisoning

Abstract

Analiza zmienności stężeń kwasu walproinowego oraz jego wybranych metabolitów w surowicy krwi pacjentów podczas terapii lekiem i w zatruciach Streszczenie Cel pracy: Porównanie profilu metabolicznego kwasu walproinowego (VPA) w badanych grupach przypadków poprzez analizę zmienności stężeń VPA z jego wybranymi metabolitami (2-en-VPA, 4-en-VPA, 3-keto-VPA). Materiał do badań: Surowica krwi pochodząca od 27 pacjentów leczonych preparatami VPA na Oddziale Psychiatrii oraz Neurologii i Udarów Mózgu WSS im. Ludwika Rydygiera w Krakowie oraz surowica krwi 26 pacjentów z podejrzeniem ostrego zatrucia VPA, hospitalizowanych w Klinice Toksykologii Katedry Toksykologii i Chorób Środowiskowych UJ CM w Krakowie. Wyniki i wnioski: Analiza wartości stężeń VPA i jego wybranych metabolitów dowodzi odmienności profilu metabolicznego VPA w ostrym zatruciu względem terapii lekiem. Jedna z dróg przemian VPA -proces desaturacji -nie ulega zmianie w ostrym zatruciu i ma przewagę nad procesem β-oksydacji. Przyjęcie dawek toksycznych VPA skutkuje wzmożonym powstawaniem 4-en-VPA proporcjonalnym do zwiększenia stężenia VPA. W ostrym zatruciu VPA dochodzi do wysycenia przemian metabolicznych VPA na etapie β-oksydacji. Proces utleniania 2-en-VPA do 3-keto-VPA ulega zwolnieniu po dawkach toksycznych.Słowa kluczowe: kwas walproinowy (VPA), profil metaboliczny, ostre zatrucie, terapia lekiem. AbstractAim of the study: To compare the metabolic profile of valproic acid (VPA) in the studied groups of cases through an analysis of variability of concentrations of VPA with its selected metabolites (2-ene-VPA, 4-ene-VPA, 3-keto-VPA). serum samples collected from 26 patients hospitalized because of suspected acute VPA poisoning at the Toxicology Department, Chair of Toxicology and Environmental Diseases, Jagiellonian University Medical College in Krakow. Results and conclusions:The analysis of concentrations of VPA and its selected metabolites has shown that the metabolic profile of VPA determined in cases of acute poisoning is different from cases of VPA therapy. One of VPA's metabolic pathways -the process of desaturation -is unchanged in acute poisoning and prevails over the process of β-oxidation. The ingestion of toxic VPA doses results in an increased formation of 4-ene-VPA, proportional to an increase in VPA concentration. Acute VPA poisoning involves the saturation of VPA's metabolic transformations at the stage of β-oxidation. The process of oxidation of 2-ene-VPA to 3-keto-VPA is slowed down after the ingestion of toxic doses.

Association of Valproic Acid and Its Main Metabolites’ Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring

“…In line with the result from a recent study in the Southern Han Chinese population (n=254), there was no significant change in 4-ene-VPA concentration in patients suffering from possible VPArelated liver injury (Ma et al, 2019). On the contrary, a small sample (n=26) study (Wilimowska, Klys, & Jawien, 2014)in Poland illustrated the rise of the 4-ene-VPA concentration in patients with drug-induced liver injury. Consistently, our prior study based on a small sample study (n=64) in the Southern Han Chinese population illustrated a positive correlation between the level of 4-ene-VPA in plasma and the occurrence of abnormal liver function test results (Chen et al, 2012).…”

Liquid chromatography–tandem mass spectrometry method for simultaneous determination of valproic acid and its ene-metabolites in epilepsy patient plasma

“…Finally, pseudo-MRM was selected for determination of VPA, 2-ene VPA and 4-ene VPA. Wilimowska [20] quantified the variabity of concentrations of VPA and its selected metabolites, 2-ene VPA and 4-ene VPA. However, no specific LC–MS/MS method was reported for simultaneous determination of VPA and its two ene-metabolites, 2-ene VPA and 4-ene VPA, in biological specimens up to date.…”