Effect of mirabegron on plasma gonadotropic and steroidal hormone levels in rats after two weeks of oral administration

摘要

The effects of mirabegron on plasma gonadotropic and steroidal hormone levels in rats were investigated, when administered orally once daily for two weeks to male and female rats at doses of 10, 30, and 100 mg/kg/day, in order to elucidate a potential mechanism for findings in the reproductive system observed in toxicity studies in rats. Significantly decreased body weight gain and food consumption were observed in males and females at 100 mg/kg/day on Days 1 to 4 of dosing. A significantly prolonged estrous interval was observed in females at 100 mg/kg/day and increased liver weights were noted in females at 30 mg/kg/day or greater. No histopathological changes were observed in the pituitary gland, adrenal glands, liver, testes, epididymides, prostate, seminal vesicle, ovaries, uterus, or vagina at any dose. In males, no treatment-related changes in levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, or dihydrotestosterone (DHT) were observed at any dose. Corticosterone levels in males increased in a dose-dependent manner at 30 mg/kg/day or greater. In females, no treatment-related changes in levels of LH, FSH, prolactin, estradiol, progesterone, or corticosterone were observed at any dose in any stage of the estrous cycle. Taken together, these results suggest that mirabegron has no effect on gonadotropic or sex steroidal hormone levels in either sex at doses up to 100 mg/kg/day. In contrast, adrenocortical hormone levels were increased in males at mirabegron doses of 30 mg/kg/day or greater.