Acetaminophen-induced hypothermia in mice: evidence for a central action of the parent compound

Pretreatment of mice with phenobarbital, an inducer of oxidative drug metabolism, had no effect on the early hypothermic effect of a toxic dose of acetaminophen, while pretreatment with metyrapone, SKF-525A, or piperonyl butoxide (inhibitors of mixed-function oxidase) enhanced the hypothermia. In mice treated with acetaminophen alone, brain parent drug levels correlated with the degree of hypothermia, while liver drug levels did not. Also, intracerebroventricular injection of acetaminophen resulted in significant hypothermia within 20 min. These results indicate that the early hypothermia caused by acetaminophen in mice is due to the parent drug, not to its toxic reactive metabolite, and that the effect is mediated centrally. The observation that piperonyl butoxide and SKF-525A themselves caused significant hypothermia indicates that the use of these compounds should be avoided when body temperature is being followed in drug metabolism experiments.