Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy

Murakami, Kiyotaka; Sugimoto, Takeshi; Nishida, Naoki; Kobayashi, Yohnosuke; Kuhara, Tomiko; Matsumoto, Isamu

doi:10.1016/s0387-7604(12)80261-0

Cited by 33 publications

(15 citation statements)

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“…[2] It was also reported that coma scene which was accompanied by hipocarnitine and ketosis that were dependant on carnitine deficiency, have emerged. [8][9][10][11][12] Slowing down in speaking, sleepiness, psychomotor retardation, progressive dizziness, general weakness, irritability, concentration weaknesses are identified findings in patients with encephalopathy. [13] The physical examination, biochemical, hormonal, serologic tests, blood gas measurement and imaging studies that we do to understand whether clinical findings identified in our patients are related to a systemic or local organ failure, were within normal limits.…”

Section: Discussionmentioning

confidence: 99%

“…While encephalopathy picture associated with carnitine deficiency is observed frequently in VPA usage, carnitine deficiency which is based on short-term VPA usage has also been reported. [8][9][10][11][12] Mitochondrial beta-oxidation is inhibited by VPA. It is thought that during chronic use of VPA, the beta-oxidation of fatty acids occurs in another way (omega-oxidation) and meanwhile, free carnitine is consumed.…”

Section: Discussionmentioning

confidence: 99%

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Primum non nocere: A case of valproate encephalopathy

Kozak¹,

Uca²

2014

Epilepsi

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Valproik asit (VPA) bazı tip epileptik nöbetlerin tedavisinde kullanılan geleneksel bir antiepileptiktir. Ensefalopati, VPA'nın nadir ancak ciddi sonuçlara yol açan yan etkilerinden biri olup hiperamonemi bu tabloya eşlik edebilir. VPA'nın ortaya çıkardığı asemptomatik hiperamonemi insidansı %20, semptomlu hiperamoniemi insidansı %5 olarak belirtilmektedir. VPA'ya bağlı hiperamoniemi patogenezi tam olarak anlaşıla-mamıştır. Bu makalede, VPA'ya bağlı ensefalopati tanısı konulan 60 yaşındaki bir erkek hasta sunuldu. Sunulan olgu, daha önce VPA kullanan ve ensefalopati tablosu izlenmeyen bir hastada tekrar ortaya çıkan nöbetlerin ardından başlanan VPA tedavisi sonrası ensefalopati ortaya çıkması yönüyle literatürde ilktir.Anahtar sözcükler: Ensefalopati; hiperamoniemi; valproik asit. SummaryValproic acid (VPA) is a traditional antiepileptic which is used in the treatment of some types of epileptic seizures. Encephalopathy is a side effect of VPA which leads to rare but serious results and hyperammoniemia may be accompanied by one of these statements. It is specified that asymptomatic hyperammoniemia which VPA revealed is 20% and the incidence of symptomatic hyperammoniemia is 5%. The reason why VPA induced hyperammoniemia pathogenesis is not fully understood. In this article we present a 60-year-old male patient who was diagnosed VPA induced encephalopathy. The case presented is the first in the literature, in that, the patient previously taking valproate and whose encephalopathy unmonitored, valproate has been used after repeated seizures; and, after that encephalopathy has emerged.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Primum non nocere: A case of valproate encephalopathy

Kozak¹,

Uca²

2014

Epilepsi

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“…Valproic acid (VPA, 2-propylpentanoic acid) has been used to treat migraines, bipolar disorder and neuropathic pain (Loscher, 1999;Murakami et al, 1992;Sugimoto et al, 1983). Its two metabolites, 4-ene-valproic acid (4-VPA; 2-propylpent-4-enoic acid) and 2,4-diene-valproic acid (2,4-VPA; 2-propyl-2,4-pentadienoic acid), are the main cause of the rare but fatal hepatotoxicity (fatty liver) of VPA (Granneman et al, 1984;Rettenmeier et al, 1985Rettenmeier et al, , 1986Zimmerman and Ishak, 1982).…”

Section: Introductionmentioning

confidence: 99%

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

Jung

Kim

Lee

et al. 2010

J of Applied Toxicology

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It has been reported that urinary excretion of two metabolites of valproic acid (VPA), 4-ene-valproic acid (4-VPA)and 2,4-diene-valproic acid (2,4-VPA), increased exponentially with the administration of high doses of VPA, and this increased formation of toxic metabolites could be related to VPA hepatotoxicity in humans. The aim of this study was to investigate whether the plasma level of 4-VPA and 2,4-VPA in rats corresponds to the urinary data for the same metabolites in humans.After the oral administration of VPA at doses of 20, 100 and 500 mg kg-1 in rats, the AUC0–24 h, 4-VPA/AUC0–24 h, VPA ratios (0.0399,0.0120 and 0.0100 for 20, 100 and 500 mg kg-1, respectively) and AUC0–24 h, 2,4-VPA/AUC0–24 h, VPA ratios (0.00104, 0.00201 and 0.00141, respectively) did not increase with increasing doses of VPA in rats. Thus, the plasma exposure of toxic metabolites normalized by dose remained unchanged (for 2,4-VPA) or even decreased (for 4-VPA) following high-dose VPA administration;this contradicts the findings of previous studies. Our results suggest that toxicity induced by high doses of VPA cannot be explained by a nonlinear increase of toxic metabolites in rats.

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“…VPA has been used to treat bipolar disorder, migraine, and neuropathic pain (Loscher et al, 1999;Murakami et al, 1992;Sugimoto et al, 1983), however, it has also been associated with fatal liver toxicity (Bryant et al, 1996;Perucca et al, 2002;Zafrani et al, 1982;Zimmerman et al, 1982). It has been widely shown that two metabolites of VPA, 4-ene VPA (2-propylpent-4-enoic acid), and 2,4-diene VPA (2-propyl-2,4-pentadienoic acid) (Fig.…”

Section: Introductionmentioning

confidence: 99%

The relationship between glucuronide conjugate levels and hepatotoxicity after oral administration of valproic acid

Lee

Kim

et al. 2009

Arch. Pharm. Res.

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The aim of this study was to investigate the relationship between hepatotoxicity, levels of glucuronide conjugates of valproic acid (VPA), and the toxic metabolites of VPA (4-ene VPA and 2,4-diene VPA). We also examined whether hepatotoxicity could be predicted by the urinary excretion levels of VPA and its toxic metabolites. VPA was administrated orally in rats in amounts ranging from 20 mg/kg to 500 mg/kg. Free and total (free plus glucuronide conjugated) VPA, 4-ene VPA, and 2,4-diene VPA were quantified in urine and liver using gas chromatography-mass spectrometry. Serum levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase (alpha-GST) were also determined to measure the level of hepatotoxicity. The serum alpha-GST level increased slightly at the 20 mg/kg dose, and substantially increased at the 100 and 500 mg/kg dose; aspartate aminotransferase and alanine aminotransferase levels did not change with the administration of increasing doses of VPA. The liver concentration of free 4-ene VPA and the urinary excretion of total 4-ene VPA were the only measures that correlated with the increase in the serum alpha-GST level (p < 0.094 and p < 0.023 respectively). From these results, we conclude that hepatotoxicity of VPA correlates with liver concentration of 4-ene VPA and can be predicted by the urinary excretion of total 4-ene VPA.

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Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy

Cited by 33 publications

References 15 publications

Primum non nocere: A case of valproate encephalopathy

Primum non nocere: A case of valproate encephalopathy

Dose‐dependent pharmacokinetics of toxic metabolites is not related to increased toxicity following high‐dose valproic acid in rats

The relationship between glucuronide conjugate levels and hepatotoxicity after oral administration of valproic acid

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