Possible Interaction: Glutamine and Valproic Acid

“ Brain glutamine concentrations were above normal in three of five patients taking valproate and two of nine taking carbamazepine or phenytoin.”

“Mean glutamine levels of patients taking valproate were higher than control subjects and patients taking carbamazepine or phenytoin.”

“ Glutamine , methionine, tyrosine, and phenylalanine CSF/plasma ratios were elevated with valproate therapy.”

“Cerebrospinal fluid/plasma ratios of glutamine and tyrosine were significantly elevated by valproate therapy and those of serine, asparagine, glutamine, valine, methionine, and phenylalanine by phenobarbital therapy.”

“It has also been reported that valproic acid can increase the transport of glutamine across the mitochondrial membrane in the kidney, thereby increasing the production of ammonia.”

“ Valproate … glutamine removal as well as the formation of ammonia, 14CO2, pyruvate, lactate and alanine, but it inhibited glucose synthesis; the increase in ammonia formation was … through glutaminase (EC 3.5.1.2) and to a much lesser extent of flux through glutamate dehydrogenase (EC 1.4.1.3).”

“The administration of 1500 mg sodium valproate to 20 patients provoked in the kidney an increased glutamine uptake correlated with an increased ammonia release, as shown by the changes of the renal arterial-venous concentration differences of glutamine and ammonia.”

“ Valproic acid induced head-shakes and increased CSF glutamine concentration.”

“Concentrations of GABA, GLU, and GLN , which were lower in EP mice than in ER mice, were significantly increased by valproate at doses of 180 and 360 mg/kg.”

“Following a 4‐day exposure to 0.6 mM valproate , the glutamine levels increased 40% and the glutamate levels 100%.”

“These effects were not directly proportional to valproate concentration, because exposure to 1.2 mM valproate resulted in a 15% decrease in glutamine levels and a 25% increase in glutamate levels compared with control cultures.”

“These results indicate that valproate increases glutaminase activity, decreases glutamine synthetase activity, and alters Krebs‐cycle activity in astrocytes, suggesting a possible mechanism for hyperammonemia in brain during valproate therapy.”

“Administration of VPA and 4-en-VPA stimulated the uptake of glutamine and glutamate and the production of ammonia by the rat kidney, resulting in an increase in the renal venous release of ammonia and in a hyperammonemia.”