Valproic acid is known to cause an increase in blood ammonia levels in humans at the usual clinical dose. In most patients, this increase is small and asymptomatic, but in some patients the increase is larger and is associated with encephalopathy. In this study, valproate also caused a small increase in blood ammonia level (from 50 to 83 μmol/l) in Wistar rats. Salicylate potentiated this increase in blood ammonia (>210 μmol/l) when coad-ministered with valproate at a dose of salicylate which did not cause a significant increase when given alone. Other nonsteroidal anti-inflammatory drugs tested (ibuprofen and naproxen) did not potentiate valproate-induced hyperammonemia, and paracetamol actually appeared to decrease ammonia levels. The degree of hyperammonemia was dependent upon diet, and fasting decreased the level of hyperammonemia. In order to determine what component of the diet was responsible for this effect, protein, fat and carbohydrate were given by gavage, individually and also a mixture of the three. Only the mixture was able to increase the degree of hyperammonemia, even though the number of calories in the mixture and in each nutrient given individually was approximately the same. 2,4-Dinitrophenol, which like salicylate uncouples oxidative phosphorylation, potentiated valproate-induced hyperammonemia at a much lower dose than salicylate. Whether salicylate can potentiate hyperammonemia and lead to encephalopathy in some patients and therefore represents one of the risk factors for observed cases of valproate toxicity remains to be determined. Potentiation of hyperammonemia by salicylates is also consistent with the apparent association between salicylates and Reye’s syndrome which is also characterized by hyperammonemia.

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