[THE EFFECTS OF THIOACETAMIDE ON THE PENTOBARBITAL SLEEPING TIME AND THE RATE OF HEPATIC DRUG-BIOTRANSFORMATION IN MICE AND RATS].

Thioacetamide is a hepatotoxic agent.In this paper,the effects of thioacetamide on the pentobarbital sleeping time and the rate of hepatic drug metabo- lism in mice and rats are reported. Mice treated with a dose of thioacetamide (60mg/kg s.c.) 48 hours prior to an in- jection of pentobarbital slept much longer than untreated animals.Similar results were obtained in rats treated 12-72 hours previous to injection.One hour after pentobarbital administration,whole-body levels of the hypnotic in thioacetamide-treated mice were significantly higher than those in control animals.The rate of biotransformation of pentobarbital in vitro by liver slices from rats pretreated with thioacetamide was found to be less rapid than those from control animals.These facts indicate that the hepatic metabolism of pentobarbital was lowered by thioacetamide pretreatment,and thus may explain,at least in part,the prolonging effect of thioacetamide on pentobarbital sleeping time.On the other hand,at the time of recovery from narcosis,the whole body levels of pentobarbital in thioacetamide pretreated mice as well as the concentrations of bar- biturate in the brain of rats pretreated similarly,were significantly lower than those in control animals.In addition,it was found that the ED-50 of pentobarbital action was decreased,and that the diethylbarbital sleeping time was increased by pretreatment with thioacetamide.It appears,therefore,that an extra-hepatic mechanism of the effect of thioacetamide on pentobarbital action is also involved. In in vitro experiments using liver slices from rats treated with thioacetamide 48 hours previously,only a slight decrease in the rate of metabolism of chlorpromazine was observed,while the rate of biotransformation of p-nitrobenzoic acid was not sig- nificantly affected.When added in vitro,thioacetamide was shown to exert no inhibitory effect on pentobarbital metabolism.The decrease in the pentobarbital-metabolizing ability of liver slices from rats pretreated with thioacetamide was found to correlate to a certain extent with the fall of hepatic glycogen and aseorbic acid contents,as well as with the histological changes induced by this hepatotoxic agent. Thioacetamide was shown not to block completely the shortening of phenobarbital sleeping time or the increase in hepatic aseorbio acid content induced by phenobarbital pretreatment.