Effect of valproate on renal metabolism in the intact dog.
Valproate is an antiepileptic drug known to induce hyperammonemia in humans. This hyperammonemia might result from a reduced detoxification of ammonium in the liver and/or from an accelerated renal ammoniagenesis. Six dogs with normal acid-base equilibrium and eight dogs with chronic metabolic acidosis were infused with valproate directly into their left renal artery in order to obtain arterial concentrations around 3 to 4 mM. The arterial ammonium concentration rose only in chronically acidotic dogs, whereas the lactate concentration and the lactate/pyruvate ratio increased in both groups. The urinary excretion of lactate and pyruvate increased markedly but the urinary excretion of other relevant metabolites remained minimal. Renal glutamine utilization and ammonium production were not changed by valproate administration in normal dogs but increased modestly in acidotic dogs. However, renal lactate utilization was drastically reduced and in fact, changed into a net production of lactate. Valproate strikingly reduced the renal cortical concentrations of glutamine, glutamate, alphaketoglutarate and citrate, and more modestly those of malate, oxaloacetate, aspartate, alanine and ATP. By contrast, the tissue lactate concentration and the lactate/pyruvate ratio were markedly increased. In experiments with brush border membrane vesicles, valproate inhibited the lactate transporter. These results suggest that high concentrations of valproate drastically inhibited the proximal reabsorption and the proximal and distal oxidation of lactate and pyruvate. Valproate probably became itself a significant energetic substrate for the kidney.
D000136:Acid-Base Equilibrium; D000138:Acidosis / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D004285:Dogs; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D010084:Oxidation-Reduction; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D014635:Valproic Acid / Q000494:pharmacology*
D007773:Lactates; D011773:Pyruvates; D019344:Lactic Acid; D014635:Valproic Acid; D000641:Ammonia; D019289:Pyruvic Acid