Carbromal is metabolized extensively in humans. The major metabolites known to date are bromoethylbutyramide, ethylbutyrylurea and inorganic bromide. After ingestion of a therapeutic dose of 1.0 g carbromal (4.2 mmoles) by four healthy volunteers highest concentrations in serum were found to be for carbromal 30 mumoles/l, for bromoethylbutyramide up to 20 mumoles/l and for ethylbutyrylurea 2--3 mumoles/l. In patients acutely poisoned by carbromal-containing sedatives serum concentrations measured were in the range of 200 mumoles/l carbromal, 350 mumoles/l bromoethylbutyramide and 50 mumoles/l ethylbutyrylurea. These patients were comatose, apneic, had isoelectric encephalographic records and decreased body temperature. The degree of central nervous depression as judged by clinical signs was found to correlate with the serum concentrations of carbromal and of bromoethylbutyramide. Pharmacological activity and acute toxicity of carbromal and its two metabolites were examined in rats and compared with the activity of phenobarbitone. For intraperitoneal injection LD-50 values were found to be for carbromal 1.8 mmoles/kg, for bromoethylbutyramide 1.5 mmoles/kg, for ethylbutyrylurea 5.0 mmoles/kg and for phenobarbitone 0.9 mmoles/kg. Carbromal and bromoethylbutyramide severely decreased body temperature. The relative narcotic activity was estimated to be for carbromal = 100; bromoethylbutyramide = 66; ethylbutyrylurea = 33; phenobarbitone = 100. The anticonvulsive activity against pentetrazol-induced generalized seizures was nearly identical for carbromal, bromoethylbutyramide and phenobarbitone. Anticonvulsant activity of ethylbutyrylurea was two to three times less than that of carbromal. Inorganic bromide was found to increase the narcotic activity of carbromal and of bromoethylbutyramide. The findings show that the clinical signs of central nervous system depression seen in patients acutely poisoned with carbromal are caused mainly by unchanged carbromal and by its metabolite bromoethylbutyramide.

The binding of carbromal and its metabolites bromoethylbutyramide and ethylbutyrylurea to human plasma proteins was investigated in vitro by use of Sephadex-gelfiltration, equilibrium dialysis and ultrafiltration. No differences appeared in the binding characteristics of human plasma and of human albumine. In a concentration range between 3.10-8 and 1.5.10-6 moles/ml about 40% of the carbromal, and in a concentration range between 3.10-8 and 1.10-5 moles/ml about 30% of the bromoethylbutyramide are bound to plasma proteins. Proteinbinding of ethylbutyrylurea was found to be less than 5%. The binding constants, Ka, to human albumine and the binding energies deltaF 0 were found to be in the range of 0.5--1.2.10(3) L/Mol and 1.7--4.4 kcal/Mol, respectively. Protein binding of carbromal, bromoethylbutyramide, their chlorinated analgous compounds, chloroethylbutyrylurea and chloroethylbutyramide, and of ethylbutyrylurea is strongly correlated to the partition coefficients of these compounds between n-octanol and water, indicating that the intensity of proteinbinding depends on the hydrophobic character of the substances tested.