The pharmacology of dichloroacetate.
Dichloroacetate (DCA) exerts multiple effects on pathways of intermediary metabolism. It stimulates peripheral glucose utilization and inhibits gluconeogeneis, thereby reducing hyperglycemia in animals and humans with diabetes mellitus. It inhibits lipogenesis and cholesterolgenesis, thereby decreasing circulating lipid and lipoprotein levels in short-term studies in patients with acquired or hereditary disorders of lipoprotein metabolism. By stimulating the activity of pyruvate dehydrogenase, DCA facilitates oxidation of lactate and decreases morbidity in acquired and congenital forms of lactic acidosis. The drug improves cardiac output and left ventricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and lactate as opposed to fat. DCA may also enhance regional lactate removal and restoration of brain function in experimental states of cerebral ischemia. DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity. DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be ameliorated or prevented with thiamine supplementation. Other toxic effects of DCA may be species-specific and reflect marked interspecies variation in pharmacokinetics. Despite its potential toxicity and limited clinical experience, DCA and its derivatives may prove to be useful in probing regulatory aspects of intermediary metabolism and in the acute or chronic treatment of several metabolic disorders.
Stacpoole
P W
PW
Department of Medicine, University of Florida, College of Medicine, Gainesville 32610.
D000085:Acetates / Q000494:pharmacology*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003999:Dichloroacetic Acid / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000506:poisoning; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000196:embryology / Q000502:physiology; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011506:Proteins / Q000378:metabolism
D000085:Acetates; D000596:Amino Acids; D007773:Lactates; D008074:Lipoproteins; D011506:Proteins; D019344:Lactic Acid; D003999:Dichloroacetic Acid