Valproate Metabolites Research Articles

Succinate transport inhibition by valproate in rat renal mitochondria

Sodium valproate is an antiepileptic drug which may have side effects on different organs. Its mechanism of action, as yet unclear, may involve an effect on membranes. One possibility, an effect on mitochondrial membranes via an inhibition of oxidative phosphorylation, has been studied here by observing the transmembranal transport of a respiratory substrate, succinate, in rat kidney mitochondria incubated with valproate, or from rats injected with valproate. Succinate transport was inhibited in both conditions, which suggests that the effect was probably due to a direct effect of valproate rather than to an action of a valproate metabolite. For the valproate-incubated mitochondria, inhibition, described by a bell-shaped curve, started at a valproate concentration of 10 −7 M and was maximum at valproate 10 −5M. Valproate's effect on mitochondrial transmembranal succinate transport can be compared to other evidence for membranal actions of valproate, actions which may clarify certain therapeutic or toxic properties of this drug.

Valproate metabolites and hepatotoxicity in an epileptic population.

Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4-en-VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4-en-VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4-en-VPA correlated with older age and absence of encephalopathy. 4-en-VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2-en-VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4-en-VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4-en-VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4-en-VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was detected only in patients receiving polytherapy, a potent risk factor for developing this rare complication.

Therapy of infantile spasms with valproate: results of a prospective study.

In a prospective study, 22 children with recently manifested infantile spasms (18 patients with symptomatic and 4 with idiopathic infantile spasms) were treated with sodium valproate (VPA). Before VPA was instituted, a loading test was performed to exclude abnormal patterns of VPA metabolites by gas chromatography and mass spectroscopy of serum and urine. This test was repeated during VPA therapy; an abnormal pattern of VPA metabolites was not observed. VPA was started in increasing dosage until infantile spasms were controlled or a maximum dose of 100 mg/kg/day was reached. If VPA did not control seizures or at least reduce frequency significantly after a trial of 4-6 weeks, dexamathasone was added to VPA. If focal seizures occurred in association with localized epileptogenic EEG discharges, carbamazepine (CBZ) was added to VPA. After 4 weeks of VPA monotherapy, infantile spasms were controlled in 11 children. After 3 months of therapy, 16 children were free of seizures (14 patients VPA monotherapy), and 4 children had reduction of seizure frequency to less than 25%. VPA doses varied between 40 and 100 mg/kg/day (mean 74). The mean plasma concentration was 113 micrograms/ml (range 46-177). After 6 months of therapy, total seizure control was achieved in 20 of 22 patients (16 children VPA monotherapy). The mean observation time was 16 1/2 months (range 6-36 months). There were seven relapses in six children during the first 7 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Valproate-associated hepatotoxicity and its biochemical mechanisms.

Intake of the anticonvulsant drug valproic acid, or its sodium salt, has been associated with occasional instances of severe and sometimes fatal hepatotoxicity. Probably at least 80 cases have occurred worldwide. The syndrome affects perhaps 1 in 10,000 persons taking the drug, and usually develops in the early weeks or months of therapy. Most instances have involved children, usually those receiving more than 1 anticonvulsant. Multiple cases have occurred in 2 families. The typical presentation is of worsening epilepsy, increasing depression of consciousness, and progressive clinical and biochemical evidence of liver failure. The liver has sometimes shown hepatocyte necrosis, and on other occasions widespread microvesicular steatosis, while cholestatic changes have also occurred. The appearances are interpreted as consistent with a drug toxicity reaction. During the hepatotoxicity increased amounts of unsaturated metabolites of valproate, notably 4-en-valproate, have been found in blood and urine. In 4 cases there has been evidence of impaired beta-oxidation of valproate with, in 1 case, accumulation of isomers of valproate glucuronide caused by intramolecular rearrangement of the conjugate. There are molecular structural similarities between 4-en-valproate and 2 known hepatotoxins (4-en-pentanoate and methylenecyclopropylacetic acid, the latter being responsible for hypoglycin poisoning). There are also clinical and histopathological similarities between valproate hepatotoxicity and both hypoglycin poisoning and certain spontaneous disorders of isoleucine metabolism (one pathway of valproate metabolism is analogous to oxidative degradation of isoleucine). Unsaturated metabolites of valproate, in particular 4-en-valproate, may contribute to the hepatotoxicity of the drug. However, since the hepatotoxicity appears to involve an element of idiosyncrasy, the primary defect in some cases may be an inherited or acquired deficiency in the drug's beta-oxidation. This defect may divert valproate metabolism towards omega-oxidation, with increased formation of the toxin 4-en-valproate, but may also allow increased formation of a toxic metabolite derived from isoleucine, since beta-oxidation of isoleucine derivatives will also be impaired.

Valproate metabolite concentrations in brain increase with chronic administration of sodium valproate

Rats were treated chronically with sodium valproate for varying periods of time up to eight weeks. A statistically significant negative correlation between plasma concentrations of valproate-derived substances (VDS) and length of treatment was observed while a statistically significant positive correlation was found between brain VDS concentration and length of treatment. Liver VDS concentrations showed a tendency to decrease with time but this trend was not statistically significant. A new procedure was developed to measure the tissue levels of VDS.

Hepatotoxicity of sodium valproate in ornithine trasncarbamylase-deficient mice

Susceptibility to sodium valproate (SV) hepatotoxicity was investigated in male sparse-fur mutant (spf/Y) mice with X-linked ornithine transcarbamylase (OTC) deficiency, as compared to normals (+/Y). SV was given in drinking water, in increasing concentrations of 0, 0.05, 0.15 and 0.25%. Actual SV intake was similar in both groups. There were no significant changes in orotate excretion, but α-amino nitrogen increased progressively with SV intake in both groups. Valproate-treated animals also had a significant increase in hepatic carbamyl phosphate synthetase- I (CPS-I) activity. OTC-deficient spf/Y mice showed 33% mortality and morbidity at 0.05–0.15% valproate, while normal mice remained non-symptomatic. spf/Y Mice also showed a higher incidence of hepatocellular necrosis, microvesicular steatosis and polymorphic infiltration. Centrilobular necrosis was seen only in symptomatic OTC-deficient mice, indicating an idiosyncratic hepatotoxic response which may be different from the dose-related effects seen in all SV-treated mice. Electron microscopy of liver sections from severely affected spf/Y mice showed marked abnormalities of mitochondria, which appeared swollen or rounded. The rough endoplasmic reticulum was dilated and filled with a flocculent material. It is postulated that the idiosyncratic response in OTC-deficient mice may be caused by an interaction between a metabolic aberration of mitochondria and toxic metabolites of valproate.

Altered metabolic profiles of valproic acid in a patient with Reye's syndrome

Urinary valproate metabolite and endogenous organic acid profiles in a 6-yr-old girl with Reye's syndrome were investigated by means of gas chromatography-mass spectrometry. 2- n-Propyl-3-oxovaleric acid, normally the major metabolite of valproate in man, was undetectable, while 2- n-propylglutaric acid, the end product via ω-oxidation was markedly increased. Polyunsaturated valproate was not found. Valproate-glucuronide was still found as the major metabolite. The clinical findings coupled with a greatly increased excretion of lactate and adipate was compatible with Reye's syndrome. Ketone bodies were not detectable. This case study shows that Reye's syndrome causes altered valproate metabolism, consistent with the defective mitochondrial β-oxidation of medium chain fatty acids, and suggests that valproic acid should not be used in the treatment of seizures in patients with this syndrome.

The toxicity of metabolites of sodium valproate in cultured hepatocytes.

Sodium valproate is hepatotoxic in both humans and rat hepatocytes. The toxicity is dose related and frequently associated with simultaneous ingestion of drugs which induce the drug metabolizing system. For these reasons, metabolites of sodium valproate were tested for toxicity using rat hepatocyte cultures. The sodium salts of three metabolites, 2-propylpent-4-enoate, 4-hydroxyvalproate, and perhaps 5-hydroxyvalproate, were toxic in this system. In addition, 2-propylpent-4-enoate was toxic in a dose-related fashion. All are omega and omega-1 oxidation products in the microsome-mediated pathway of valproate metabolism.