The treatment of male rats with estradiol resulted in an increased hypothermic res onse to chlorpromazine. This increased pharmacologic response appears to ge due to a decreased metabolism of chlorpromazine as indicated by the increased blood ievels of S-35 after S-35 chlorpromazine administration and a decreased in vitro metabolism of chlorpromazine by liver microsomes from treated rats. N o significant change was observed in the total liver or microsomal protein content.
There is indication that decreased NADPH oxidase activity may be involved.
OST OF the studies involving the effect of sex hormones on drug metabolism were attempts to explain sex differences in drug responses. Axelrod (1) studied the effect of sex hormones on the in vitro N-demethylation of methadone, meperidine, and morphine in liver microsomes. The treatment of male rats with estradiol decreased this metabolic activity.
Murphy and DuBois (2) found that pretreatment with estrogen had a similar effect on the enzymes responsible for the oxidation of gluthion. Estrogen also decreases the metabolism of hexobarbital in liver microsomes from male rats (3,4).
Hyvert et al. (5) reported that female patients
responded more satisfactorily than male patients to chlorpromazine treatment. Also, male patients treated with estrogens had more satisfactory responses to chlorpromazine therapy than did males not on estrogen treatment. Berti and Cima (6) reported that lesser amounts of the demethylated chlorpromazine derivatives and/or their sulfoxides were detected in the livers and brains of female rats as compared to the same organs in male rats. Thus, the objective of this study was t o determine the effect of estrogen treatment on hypothermia, tissue distribution, and metabolism of chlorpromazine in the rat.
Methods
Male Holtzman rats, weighing 240 to 250 Gm., were given 25 mcg. of estradiol valerate in sesame oil by intramuscular injection a t 5-day intervals and control animals received injections of sesame oil. The hypothermia was determined by measuring colonic temperature with a telethermometer and thermistor probe a t 1-hr. intervals after an intraperitoneal injection of chlorpromazine hydrochloride.
The tissue uptake and plasma level studies were determined with S-35 chlorpromazine after 3 weeks