Hideki Muro

Effect of L-carnitine supplementation on acute valproate intoxication.

Summary: We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4‐en VPA, the presumed major factor in VPA‐induced hepato‐toxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased β‐oxidation and markedly increased ω‐oxidation. After L‐carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L‐carnitine. L‐Carnitine may be useful in treating patients with coma after VPA overdose.

Determination of valproic acid and its metabolites by gas chromatography—mass spectrometry with selected ion monitoring

A modified method for the determination of valproic acid, its eleven metabolites and their conjugates in small samples of serum and urine by gas chromatography-mass spectrometry with selected-ion monitoring was developed. Valproic acid and its eleven metabolites were determined in serum and urine of epileptic patients treated with valproic acid. 2-Hydroxy-2-propylpentanoic acid was identified as a new metabolite of valproic acid in the urine of 11 of the 12 patients. The unsaturated metabolites, such as (Z)- and (E)-2-propyl-2-pentenoic acid, were found to be predominantly excreted as glucuronides. 3-Hydroxy-2-propylpentanoic acid and 2-propylglutaric acid were also excreted as glucuronides.

Valproate Metabolites in High‐Dose Valproate Plus Phenytoin Therapy

Summary: Purpose: We wished to determine the relation between liver function, β‐, and ω‐, and ω‐1‐oxidation metabolites and 4‐en‐valproate (VPA).

Metabolite profiles in patients on high-dose valproate monotherapy

To investigate the mechanism of valproate (VPA)-induced hepatotoxicity, we measured the serum and urine metabolites of VPA in high-dose VPA monotherapy by GC/MS/SIM and discussed the relationship between liver function and beta-oxidation, omega-, (omega-1)-oxidation metabolites and 4-en-VPA. In high-dose VPA monotherapy, the concentrations of beta-oxidation metabolites were not increased except for 2-en-VPA, but the concentrations of {omega + (omega-1)}-oxidation metabolites and of 4-en-VPA were increased about 4-5 times compared to those of standard dose VPA monotherapy. Serum GOT was not significantly correlated to 4-en-VPA and the ratio of beta-oxidation/{omega + (omega-1)} oxidation metabolites of VPA in serum. In high-dose VPA monotherapy, it is speculated that the beta-oxidation of VPA in the mitochondria reached the saturation point. However, instead of the beta-oxidation, the {omega + (omega-1)}-oxidation in microsomes was increased. We could not find significant relationship between the formation of toxic metabolites of VPA and liver dysfunction. Our data in VPA monotherapy suggest that the mechanisms of VPA-induced fatal hepatotoxicity cannot be explained by decreased beta-oxidation, increased omega-oxidation and increased 4-en-VPA level.

Determination of urinary valproylcarnitine by gas chromatography-mass spectrometry with selected-ion monitoring

A modified method for the determination of valproylcarnitine in urine samples of patients receiving sodium valproate by gas chromatography-mass spectrometry with selected-ion monitoring is described. The chemically analogous internal standard 2-ethylpentanoylcarnitine was added to the urine samples. Valproic acid and its metabolites were removed by extraction with chloroform at pH 5.0. The samples were then applied onto a C18 Sep-Pak column. Inorganic and water soluble compounds were washed out with water. Valproylcarnitine and internal standard were eluted with methanol and were derivatized to the corresponding acyl-containing lactones by heating at 100 degrees C for 60 min in dimethylformamide. Urinary valproylcarnitine levels of epileptic patients receiving valproate were determined according to the present method. The data obtained might be useful for diagnosis of carnitine deficiency.