Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.
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.
Ishii
Shun-ichiro
S
Safety Research Laboratory (Kazusa), Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba, Japan. Ishii.Shunichiro@mf.mt-pharma.co.jp
Ube
Masayuki
M
Okada
Miyoko
M
Adachi
Tamiko
T
Sugimoto
Jiro
J
Inoue
Yoshimi
Y
Uno
Yoshifumi
Y
Mutai
Mamoru
M
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004334:Drug Administration Schedule; D004622:Embryo, Mammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D005497:Follicular Cyst / Q000139:chemically induced / Q000473:pathology; D006966:Hyperprolactinemia; D007564:Japan; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D013469:Sulpiride / Q000008:administration & dosage / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*
D014150:Antipsychotic Agents; D013469:Sulpiride