Abstract
Carbromal-C14 has been synthesized and used in studies of the metabolism of carbromal.
Paper chromatograms of extracts of blood from mice after administration of carbromal-C14 showed the presence of two major metabolites, one the previously identified metabolite, 2-ethylbutyrylurea, and the other a hitherto unrecognized metabolite.
A crystalline substance having the chromatographic characteristics of the unknown metabolite in mouse blood was isolated from the urine of a dog that had received unlabeled carbromal. It was identified as one of the racemic forms of 2 - bromo - 2 - ethyl - 3 - hydroxybutyrylurea ("hydroxycarbromal").
Carbromal is rapidly converted by the mouse into 2-ethylbutyrylurea and hydroxycarbromal. The concentration of the former is a little higher than that of the latter in blood. Carbromal is metabolized more slowly by the rat than by the mouse, and a smaller proportion is converted to hydroxycarbromal.
Mouse liver slices produced both metabolites in vitro. Mouse kidney slices produced only 2-ethylbutyrylurea. No production of either metabolite could be demonstrated with mouse spleen, lung, brain, heart, or muscle. Heating abolished the ability of mouse liver and kidney to metabolize carbromal. A preparation of the microsomal and soluble fractions of mouse liver homogenate with added NADP, glucose-6-phosphate, and nicotinamide under an atmosphere of oxygen produced both metabolites.
Slices of rat liver, spleen, and kidney produced 2-ethylbutyrylurea but no detectable amounts of hydroxycarbromal. Rat lung, brain, heart, and muscle produced neither metabolite.
Slices of dog liver produced 2-ethylbutyrylurea and questionably detectable amounts of hydroxycarbromal. Dog kidney, spleen, and lung produced neither metabolite.
No nonenzymatic reduction of carbromal at physiological temperature and pH could be demonstrated with cysteine, glutathione, ascorbic acid, or NADH.
It is suggested that the fact that the homolytic fission of the carbon-halogen bond with replacement of halogen by hydrogen occurs only enzymatically with carbromal may account for the lack of toxicity characteristic of compounds such as carbon tetrachloride in which the reaction can occur nonenzymatically.
Footnotes
- Received August 5, 1963.
- Accepted September 23, 1963.
- The Williams & Wilkins Company
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