Circadian rhythms in drug action and drug metabolism in the mouse

The relationship between circadian rhythms in the pharmacological actions of meperidine and hexobarbital and similar rhythms in the hepatic metabolism of these drugs was examined in mice under a variety of environmental alterations to determine whether such rhythms may be causally related. The rate of metabolism of p-nitroanisole and hexobarbital by hepatic 9000 X g supernatant fractions was found to be higher at 2400 hours (middark phase) compared to 1200 hours (midlight phase). The rhythms in in vitro hexobarbital and in vivo merperidine metabolism were inversely related in time with similar rhythms in duration of hexobarbital sleep time and meperidine analgesia. Exposure of mice to continuous lighting abolished the rhythms in metabolism and response to meperidine and hexobarbital. Reversal of the usual lighting cycle inverted the rhythm in hexobarbital metablism while abolishing the rhythm in pharmacological response to hexobarbital; meperidine was similarly affected. Adrenalectomy abolished the rhythm in hexobarbital metabolism, diminished the amplitude of the circadian variation in meperidine metabolism and abolished the rhythm in hexobarbital hypnosis and meperidine analgesia. These results indicate that circadian rhythms in the action of hexobarbital and meperidine are well correlated with similar rhythms in the disposition of these drugs.