DISTRIBUTION AND METABOLISM 629 



lactate, ammonium chloride, magnesium sulfate, sodium bicarbonate, and 

 dimercaprol [ ! ], but no protection or benefit was observed, which is not 

 very surprising. It would be interesting to know if either fumarate or malate, 

 the products of succinate oxidation and possible restorers of cycle activity, 

 is effective. Barbital controls the convulsions produced by dehydroacetate 

 and allows recovery from an otherwise fatal dose, indicating that the con- 

 vulsions must contribute to the death of the animals. 



DISTRIBUTION AND METABOLISM 



Whether given orally or parenterally, during acute or chronic administra- 

 tion, most of the dehydroacetate seems to be metabolized in the body, since 

 less that 25% is found in the urine (monkeys 10%, dogs 20%, man 22%) 

 and only around 5% in the feces (Shideman et at., 1950 a,b). Only insignifi- 

 cant amounts of conjugated dehydroacetate occur in the urine inasmuch as 

 2-4% more can be obtained on acid hydrolysis. It was not possible to de- 

 monstrate destruction of dehydroacetate by slices of rat liver, kidney, or 

 brain, or in muscle mince in incubations up to 4 hr, although, as pointed out, 

 the analyses may not have been specific enough to have detected certain 

 chemical modifications. No evidence could be found for the appearance of 

 2,6-dimethyl-l,4-pyrone or 6-methyl-2^-pyran-2,4(3/f)-dione, substances 

 formed in the chemical degradation of dehydroacetate. Nor were positive 

 tests for acetomalonate or acetoacetate, two possible metabolic products, 

 obtained in dog or human urine. The stimulation of liver and muscle respi- 

 ration by dehydroacetate might indicate metabolism of dehydroacetate in 

 these tissues, but this is not at all certain. However, it has been shown that 

 in animals with carbon tetrachloride liver damage the toxicity of dehydro- 

 acetate is increased 29%, pointing to the liver as at least one site for the 

 metabolism. 



The oral administration to rats of small doses (60 mg/kg) of dehydroace- 

 tate, labeled in four of its carbon atoms, leads after 5 days to the following 

 distribution of the label: urine 23%, feces 19%, carcass 22%, and respira- 

 tory CO2 12.4% (Barman et al., 1961). The urine contains five labeled sub- 

 stances: unchanged dehydroacetate (4.7%), hydroxydehydroacetate (7%), 

 triacetic acid lactone (1.2%), urea (0.2%), and an unknown pyrone meta- 

 bolite (the figures in parentheses give the percentages of the dose). In ad- 

 dition, the imino derivatives of dehydroacetate and hydroxydehydroacetate 

 are found, since reaction with ammonia occurs in the urine. The major 

 metabolic pathway was postulated to be 



Dehydroacetate -► hydroxydehydroacetate -> triacetic acid lactone -> 

 acetoacetate + acetate 



The hydroxylation of the S-COCHg group occurs in slices of liver, but not 



