Collaborative work on evaluation of ovarian toxicity 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats

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  • Ishii Shun-ichiro
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation
  • Ube Masayuki
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation
  • Okada Miyoko
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation
  • Adachi Tamiko
    Safety Research Laboratory (Kashima), Mitsubishi Tanabe Pharma Corporation
  • Sugimoto Jiro
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation
  • Inoue Yoshimi
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation
  • Uno Yoshifumi
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation
  • Mutai Mamoru
    Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation

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To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

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