Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 3 No. 1 January 26, 2016 p.19-25
Original Article
A study on the influence of acotiamide hydrochloride hydrate on sex hormones, using a uterotrophic bioassay in rat
  • Hiroyuki Kuroda (R&D PLANNING, Zeria Pharmaceutical Co., Ltd. /
Hiroyuki Kuroda 1) , Takashi Yamaguchi 2) , Toshiko Kinomoto 2) , Shuji Ogawa 2) , Hitoshi Naraoka 3) , Kazuhiko Takamatsu 3) , Yuji Oishi 3)
1) R&D PLANNING, Zeria Pharmaceutical Co., Ltd. , 2) Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd. , 3) Drug Safety Research Laboratories, Astellas Pharma Inc.
Keywords: Acotiamide, Endometrial adenocarcinoma, Rat, Carcinogenicity, Sex hormone

Acotiamide hydrochloride hydrate (acotiamide-HH) is the first approved drug in the world for the treatment of patients with functional dyspepsia in Japan. A statistically significant increase in the incidence of endometrial adenocarcinoma was found in a 104-week carcinogenicity study in rats, in a non-dose-dependent manner, and it was considered that further evaluation was required to clarify this issue. Therefore, we performed a uterotrophic bioassay using immature female rats, which is mentioned in the Organization for Economic Co-operation and Development (OECD) Guideline 440, to evaluate the effect of acotiamide-HH on estrogen, which is one of the most important mechanisms causing increase in the incidence of endometrial adenocarcinoma. The positive control substance selected was 17α-ethinyl estradiol (EE). While EE caused a dose-dependent increase in uterine weight, no increase in uterine weight, histopathological changes, or endometrial proliferation activity were observed in the acotiamide-HH treatment groups at doses of up to 1000 mg/kg. Based on this result, we concluded that acotiamide-HH has no potential risk to cause imbalance of the sex hormone environment in female rats.