Valproic acid (VPA; 2-n-propylpentanoic acid) is widely used as a major drug in the treatment of epilepsy and in the control of several types of seizures. Being a simple fatty acid, VPA is a substrate for the fatty acid β-oxidation (FAO) pathway, which takes place primarily in mitochondria. The toxicity of valproate has long been considered to be due primarily to its interference with mitochondrial β-oxidation. The metabolism of the drug, its effects on enzymes of FAO and their cofactors such as CoA and/or carnitine will be reviewed. The cumulative consequences of VPA therapy in inborn errors of metabolism (IEMs) and the importance of recognizing an underlying IEM in cases of VPA-induced steatosis and acute liver toxicity are two different concepts that will be emphasized.

Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review

Acute valproic acid intoxication is an increasing problem, accounting for more than 5000 calls to the American Association of Poison Control Centers in 2000. The purpose of this paper is to review ...

Valproic Acid Toxicity: Overview and Management

Background – Drug-induced liver injury associated with antiepileptic drugs (AED) is well recognized. The frequency of the most common AED is rare but the consequences can be very serious leading to death or liver transplantation due to acute liver failure induced by these drugs.

Clinical features –  Hypersensitivity features are found in more than 70% of patients with phenytoin-induced liver injury, whereas this is only observed in 30% of carbamazepine-associated hepatotoxicity and very rarely with valproate (VPA)-induced liver injury.

Pathophysiology –  The underlying mechanisms behind hepatotoxicity induced by AED are not clear. Reactive metabolites from AED can, in some cases, lead to direct cytotoxicity and liver cell necrosis, whereas in other cases this may lead to neoantigen formation inducing immunoallergic mechanisms.

Treatment –  No specific therapy is of proved value in severe hepatotoxicity due to AED. However, N-acetylcystein is an appropriate treatment in patients with clinically significant liver injury due to phenytoin and carbamazepine. In patients with VPA-associated liver injury, carnitine that is an important co-factor in the mitochondrial beta-oxidation of fatty acids is the recommended treatment. Early referral of patients with severe liver reactions and coagulopathy to liver transplant centers before encephalopathy can be the difference between liver transplantation and death.

Hepatotoxicity associated with antiepileptic drugs

Lamotrigine for the treatment of epilepsy in childhood

Several different factors, including pharmacogenetics, contribute to inter-individual variability in drug response. Like most other agents, many antiepileptic drugs (AEDs) are metabolised by a variety of enzymatic reactions, and the cytochrome P450 (CYP) superfamily has attracted considerable attention. Some of those CYPs exist in the form of genetic (allelic) variants, which may also affect the plasma concentrations or drug exposure (area under the plasma concentration-time curve [AUC]) of AEDs. With regard to the metabolism of AEDs, the polymorphic CYP2C9 and CYP2C19 are of interest. This review summarises the evidence as to whether such polymorphisms affect the clinical action of AEDs. In the case of mephenytoin, defects in its metabolism may be attributable to >10 mutated alleles (designated as *2, *3 and others) of the gene expressing CYP2C19. Consequently, poor metabolisers (PMs) and extensive metabolisers (EMs) could be differentiated, whose frequencies vary among ethnic populations. CYP2C19 contributes to the metabolism of diazepam and phenytoin, the latter drug also representing a substrate of CYP2C9, with its predominant variants being defined as *2 and *3. For both AEDs, there is maximally a 2-fold difference in the hepatic elimination rate (e.g. clearance) or the AUC between the extremes of EMs and PMs which, in the case of phenytoin (an AED with a narrow ‘therapeutic window’), would suggest a dosage reduction only for patients who are carriers of mutated alleles of both CYP2C19 and CYP2C9, a subgroup that is very rare among Caucasians (about 1% of the population) but more frequent in Asians (about 10%). The minor contribution of CYP2C19 to the metabolism of phenobarbital (phenobarbitone) can be overlooked. In rare cases, valproic acid can be metabolised to the reactive (hepatotoxic) metabolite, 4-ene-valproic acid. It is not yet clear whether genetic variants of the involved enzyme (CYP2C9) are responsible for this problem. Likewise, the active metabolite of carbamazepine, carbamazepine-10, 11-epoxide, is transformed by the microsomal epoxide hydrolase, an enzyme that is also highly polymorphic, but the pharmacokinetic and clinical consequences still need to be evaluated.

The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications.

Valproic acid (VPA) is widely used as an anticonvulsant, but therapy with the drug has been associated with hepatotoxicity, either reversible hepatic dysfunction or irreversible hepatic failure. Both clinical and experimental studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of the beta-oxidation and synthesis of fatty acids and inhibition of gluconeogenesis, urea synthesis, oxidative phosphorylation, and the glycine cleavage system. Other abnormalities noted include alteration in the protein conformation of the internal mitochondrial membrane, hyperammonemia, and increased bile flow. The mechanisms of such hepatotoxicity, whether mediated by VPA or by its metabolites, are still little understood. Susceptibility to VPA hepatotoxicity may be enhanced by such conditions as starvation, inborn errors of metabolism, additional neurological disease, and concomitant administration of enzyme-inducing drugs.

Valproic acid and the liver.

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Valproic acid and the liver.