The potentiation of barbiturate-induced narcosis by procarbazine

Abstract

Procarbazine (MIH), N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (NSC-77213), a clinically effective antineoplastic agent, induced sleep in mice at its optimally effective dose (400 mg/kg) and prolongs hexobarbital sleeping times. MIH (400 mg/kg) increased the period of sleep following hexobarbital (100 mg/kg) nearly 10-fold. Nonhypnotic doses of MIH also significantly prolonged hexobarbital-induced sleep. Hexobarbital half-life in plasma was prolonged 6 to 7 times by prior treatment with MIH (400 mg/kg). Liver microsomes from mice treated with MIH exhibited decreased metabolism of the following substrates in vitro: hexobarbital, aminopyrine, ethylmorphine, and aniline. Cytochrome P-450 levels were also decreased by MIH treatment. Maximal decreases in enzyme activity and P-450 content occurred between 4 and 8 hours following treatment. Pretreatment with phenobarbital decreased the effectiveness of MIH to prolong hexobarbital sleeping times while pretreatment with SKF 525A added to the potentiating effect of MIH. Two major metabolites of MIH had neither central nervous system hypnotic effect nor inhibited hepatic microsomal mixed-function oxidases. Therefore, MIH potentiation of hexobarbital-induces sleep is probably due both to its direct hypnotic effect and inhibition of mixed-function oxidase activity.