Yuno Koichiro, Onishi Yuko, Arima Akihiro, Zaizen Kinuko, Aoki Yoshinobu, Nakagawa Soichi, Schneidkraut Marlowe J, Miyamae Yoichi
Drug Safety Research Laboratories, Astellas Pharma Inc.
J Toxicol Sci. 2014 Jun;39(3):507-14. doi: 10.2131/jts.39.507.
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.
为阐明在大鼠毒性研究中观察到的生殖系统相关发现的潜在机制，研究了米拉贝隆对大鼠血浆促性腺激素和甾体激素水平的影响。以10、30和100mg/kg/天的剂量，对雄性和雌性大鼠每日口服给药一次，持续两周。给药第1至4天，100mg/kg/天剂量组的雄性和雌性大鼠体重增加和食物摄入量显著降低。100mg/kg/天剂量组的雌性大鼠发情间期显著延长，30mg/kg/天及以上剂量组的雌性大鼠肝脏重量增加。各剂量组的垂体、肾上腺、肝脏、睾丸、附睾、前列腺、精囊、卵巢、子宫或阴道均未观察到组织病理学变化。在雄性大鼠中，各剂量组的黄体生成素（LH）、卵泡刺激素（FSH）、睾酮或双氢睾酮（DHT）水平均未观察到与治疗相关的变化。30mg/kg/天及以上剂量组的雄性大鼠皮质酮水平呈剂量依赖性增加。在雌性大鼠中，发情周期各阶段的任何剂量组均未观察到LH、FSH、催乳素、雌二醇、孕酮或皮质酮水平与治疗相关的变化。综上所述，这些结果表明，在高达100mg/kg/天的剂量下，米拉贝隆对两性的促性腺激素或性甾体激素水平均无影响。相比之下，米拉贝隆剂量为30mg/kg/天及以上时，雄性大鼠的肾上腺皮质激素水平升高。
