Valproate hepatotoxicity syndrome: Hypotheses of pathogenesis

Stephens, Jeffrey R.

doi:10.1007/bf01962700

Cited by 33 publications

(19 citation statements)

References 42 publications

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“…However, VPA causes severe liver damage in some patients (1,2). Its association with Reye's syndrome has also been reported (3).…”

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confidence: 90%

“…E-mail: italmeida@ff.ul.pt. 2 Abbreviations used: VPA, 2-n-propylpentanoic acid or valproic acid; ⌬ 2 -VPA, 2-n-propyl-2-pentenoic acid; 3-OH-VPA, 3-hydroxy-2-n-propylpentanoic acid; 3-keto-VPA, 3-keto-2-n-propylpentanoic acid; CoA, coenzyme A; DTNB, 5,5Ј-dithiobis(2-nitrobenzoic acid); HPLC, high-performance liquid chromatography; GC-MS, gas chromatography-mass spectrometry; FAB-MS, fast atom bombardment-mass spectrometry; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; BCA, bicinchoninic acid; Mops, 4-morpholinepropanesulfonic acid; BSA, bovine serum albumin; Mes, 4-morpholineethanesulfonic acid.…”

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confidence: 97%

“…Valproate (2-n-propylpentanoate; VPA) 2 is a widely used anticonvulsant drug. However, VPA causes severe liver damage in some patients (1,2).…”

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confidence: 99%

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Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Silva

Ruiter

IJlst

et al. 2001

Analytical Biochemistry

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“…However, VPA causes severe liver damage in some patients (1,2). Its association with Reye's syndrome has also been reported (3).…”

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confidence: 90%

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confidence: 97%

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Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Silva

Ruiter

IJlst

et al. 2001

Analytical Biochemistry

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“…The therapeutic use of VPA may lead to a rare but fatal hepatotoxicity that is characterized by steatosis with or without necrosis of the liver. 2 Risk factors associated with VPA-induced hepatotoxicity include an age of less than 2 years, multiple anticonvulsant drug therapy, and concurrent medical disorders. 3 The mechanism of VPA-induced hepatotoxicity is not known, but it has been postulated that 4-ene-VPA, which is an oxidative metabolite of VPA, may be biotransformed to an electrophilic diene that inhibits mitochondrial b-oxidation enzymes and depletes cellular gluthathione.…”

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confidence: 99%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9*2 and CYP2C9*3 variants were less efficient than the CYP2C9*1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9*2 was due to a reduced Vmax, whereas, in the case of CYP2C9*3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9*2 and CYP2C9*3 genotypes may compromise hepatic VPA biotransformation.

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“…In this special subpopulation, the risk of fatal hepatotoxicity is -1 :600 (2,3). VPA-induced hepatotoxicity results from the unsaturated metabolites, 4-ene VPA and 2,4-diene VPA, which interfere with the liver's normal metabolic function (3)(4)(5). The other inajor adverse effect associated with VPA therapy is congenital malformations appearing in the offspring of women with epilepsy taking VPA for seizure control during the first trimester of pregnancy (6).…”

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Structure‐Pharmacokinetic‐Pharmacodynamic Relationships of yV‐Alkyl Derivatives of the New Antiepileptic Drug Valproyl Glycinamide

1999

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Summary: Piirpo.sc: The purpose of this study was to evaluate the structure-pharmacokinetic-pharniacodynamic relationships of a series o f N-alkyl and N,N-dialkyl derivatives of the new antiepileptic drug (AED), valproyl glycinamide (VGD). Method.s:The following compounds were synthesized: Nmethyl VGD (M-VGD), N,N-dimethyl VGD, N-ethyl VGD. N,N-diethyl VGD (DE-VGD), and N.N-diisopropyl VGD. These compounds were evaluated for anticonvulsant activity. neurotoxicity, and pharmacokinetics.Ke.su1r.s: After i.p. administration to mice in the maximal electroshock seizure test (MES), DE-VGD had an ED,,, value comparable to that of VGD ( I 45 and 152 mg/kg, respectively), whereas in the subcutaneous metrazol test (sc Met) model, M-VGD had a slightly lower ED,,, than VGD (108 and 127 mg/kg, respectively). After oral administration to rats, M-VGD had an MES-ED,,, similar to that of VGD (75 and 73 mg/kg, respectively). Of the N-alkyl VGD derivatives stiidied, M-VGD had the best pharmacokinetic profile: the lowest clearance (5.4 L/h), the longest half-life (1.8 h). and the lowest liverextraction ratio ( 14%). N,N-dialkylated VGD derivatives uiiderwent two consecutive N-dealkylations, whereas N-alkylated derivatives underwent a single N-dealkylation process, yielding VGD as a major active metabolite.Conc1usion.c.: M-VGD had the most favorable pharmacodynamic and pharmacokinetic profile of the investigated N-alkyl VGD derivatives. VGD was found to be a major active metabolite of M-VGD and to be less neurotoxic than M-VGD. Therefore VGD rather than one of the investigated N-alkyl VGD derivatives should be considered for development as a new AED. Key Words: Valproyl glycinatnide-Metabolic Nde a I k y I ii t i o n-P h iir in ac o k i ne tic s-S t ru c t u re-P harm ac o k inetic-Pharmacodynamic relationships.Valproate (VPA), in addition to phenobarbital, phenytoin (PHT), and carbamazepine, is one of the four major antiepileptic drugs (AEDs). Despite its lower potency compared with other major AEDs (in the classic animal models for AED screening), VPA has a broad spectrum of antiepileptic activity and is clinically used in various types of epilepsy and other central nervous system (CNS) disorders (1). VPA therapy has been associated with two rare but severe adverse effects: hepatotoxicity and teratogenicity. Because of these severe adverse effects, the use of VPA has been restricted in two subpopulations: children younger than 2 years and women of childbearing age. Hepatotoxicity, the most serious and fatal adverse effect of VPA, occurs predominantly in children younger than 2 years receiving polytherapy for their seizure disorder. In this special subpopulation, the risk of fatal hepatotoxicity is -1 :600 (2,3). VPA-induced hepatotoxicity results from the unsaturated metabolites, 4-ene VPA and 2,4-diene VPA, which interfere with the liver's normal metabolic function (3-5). The other inajor adverse effect associated with VPA therapy is congenital malformations appearing in the offspring of women with epilepsy taking VPA for seizur...

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Valproate hepatotoxicity syndrome: Hypotheses of pathogenesis

Cited by 33 publications

References 42 publications

Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Synthesis and Intramitochondrial Levels of Valproyl-Coenzyme A Metabolites

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Structure‐Pharmacokinetic‐Pharmacodynamic Relationships of yV‐Alkyl Derivatives of the New Antiepileptic Drug Valproyl Glycinamide

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