Renal and systemic acid-base effects of chronic dichloroacetate administration in dogs.
Dichloroacetate (DCA) increases metabolic disposal of lactic acid secondary to activation of pyruvate dehydrogenase and consequent acceleration of pyruvate oxidation. DCA has thus been proposed as a therapeutic agent for clinical states of lactic acidosis. Yet, DCA has a potential metabolic acidosis-producing effect by virtue of reported effects of (A) increasing blood ketoacid concentration, (B) decreasing tubular reabsorption of filtered ketoacid anions, and (C) decreasing renal NH3 production. In the present study chronic administration of DCA, 50 mg/kg p.o. daily for 6-8 days, resulted in a cumulative increase in renal net acid excretion (NAE) (sigma delta NAE, +61 meq, p < 0.05). The increase in NAE was accounted for entirely by increased NH4+ excretion. Production of ammonia by the kidney appeared to be increased since the increased excretion of NH4+ was accompanied by an increase in urine pH (delta UpH, +0.18 +/- 0.07, p < 0.05). The increase in NAE was accompanied by a nearly identical increase in urinary anion gap (UAG) (UAG = [NH4+ + Na+ + K+] - [Cl- + HCO3- + HPO4(2-) + H2PO4-]). The increase in UAG was caused by increased urinary total organic anions, accounted for at least in part by a significant increase in urinary acetoacetate. No significant increase in urinary potassium or sodium excretion occurred. A change in plasma acid-base composition occurred that was consistent with a mild respiratory acidosis without associated primary metabolic acidosis or alkalosis. These findings indicate that chronic DCA administration results in (1) increased steady state endogenous noncarbonic organic acid production, and (2) retention of carbonic acid. Further investigation of the potential metabolic and respiratory acidosis-producing effects of DCA is required to determine its clinical efficacy in the treatment of clinical lactic acidosis.
D000085:Acetates / Q000494:pharmacology*; D000136:Acid-Base Equilibrium / Q000187:drug effects*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004285:Dogs; D004573:Electrolytes / Q000097:blood / Q000652:urine; D005260:Female; D007668:Kidney / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D000085:Acetates; D002712:Chlorides; D004573:Electrolytes; D003999:Dichloroacetic Acid; D012964:Sodium; D011188:Potassium; D002118:Calcium