Effect of heat and restriction of movement on barbital distribution and metabolism in the rat



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Chronic environmental stress has been reported in human subjects to cause altered drug activity, duration of action and toxicity. The purpose of the present study was to determine the extent to which chronic heat and restriction stress would alter barbital activity. Furthermore, an attempt was made to elucidate the mechanism of altered drug action with respect to speed of drug absorption, distribution and excretion and drug metabolism. Albino rats were stressed for fourteen days by partial restriction of movement in an environment maintained at 32° ± 2° C., relative humidity 15-20 per cent. Control rats were maintained under conditions which were relatively "stress-free". The effects of the above two animal treatments on induction time, duration of action and toxicity of barbital sodium (250 mg/kg; I.P.) were studied. The drug was injected 2 hours and 26 hours after removal from stress. Radioactive barbital-2-C-14 injected with the second of the above doses. The distribution of the tracer was estimated at various time interv.ils after injection in brain, liver, kidney and plasma. The experimental agent, beta-diethylaminoethyl diphenylpropylacetate hydrochloride (SKF 525A), a liver microsomal enzyme inhibitor was injected into certain stressed and non-stressed rats, 45 minutes before, each of the two injections of barbital sodium. Urine, collected from rats subjected to the above treatments, was assayed qualitatively and quantitatively for the presence of barbital metabolites. Under the conditions of the present experiment, the following observatiors were made: 1. The highest barbital concentrations in brain, liver and plasma occurred at about 120, 20 and 20 minutes after injection, respectively in each treatment group; 2. The highest barbital concentration in the kidney was found at 20 minutes in stressed rats, and 120 minutes in non-stressed rats; 3. The highest ratio of brain barbital to plasma barbital occurred at 120 minutes in all animals except non-SKF 525A pre-treated animals; 4. The excretion of Carbon-14 after injection of barbital-2-C-14 did not differ appreciably in stressed or SKF 525A pre-treated rats; 5. The urinary excretion of barbital metabolites did not differ appreciably in stressed and SKF 525A pre-treated animals; 6. Prolongation of the duration of barbital hypnosis by pre-treatment with SKF 525A was correlated with an increase of plasma and brain levels of barbital in the SKF 525A pre-treated rats.