title: Collaborative work on evaluation of ovarian toxicity. 15) Two- or four-week repeated-dose studies and fertility study of bromocriptine in female rats.
abstract: The main focus of this study is to determine the optimal administration period concerning toxic effects on ovarian morphological changes in a repeated-dose toxicity study. To assess morphological and functional changes induced in the ovary by bromocriptine, the compound was administered to female rats at dose levels of 0, 0.08, 0.4 and 2 mg/kg for the 2- or 4-week repeated-dose toxicity study, and for the female fertility study from 2 weeks prior to mating to day 7 of gestation. In the 2-week repeated-dose toxicity study, increase of ovarian weights was observed at 2 mg/kg. In the 4-week repeated-dose toxicity study, ovarian weights were increased at 0.4 and 2 mg/kg. The number of corpora luteum was increased in the 0.4 and 2 mg/kg groups of the 2- and 4-week repeated-dose toxicity studies by histopathological examination of the ovaries. Bromocriptine did not affect estrous cyclicity in 2- and 4-week repeated dosing. In the female fertility study, although animals in any groups mated successfully, no females in 0.4 and 2 mg/kg groups were pregnant. There were no adverse effects on reproductive performance in the 0.08 mg/kg group. Based on these findings, the histopathological changes in the ovary are considered important parameters for evaluation of drugs including ovarian damage. We conclude that a 2-week administration period is sufficient to detect ovarian toxicity of bromocriptine in a repeated-dose toxicity study.
authors.affiliation: Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Inabe-shi, Mie, Japan. t_kumazawa@m4.skk-net.com
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kumazawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishiguro
authors.forename: Zhu
authors.initials: Z
authors.lastname: Jiuxin
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaharu
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nishitani
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Inoue
authors.forename: Satoko
authors.initials: S
authors.lastname: Harada
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hayasaka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000633:toxicity*; D001971:Bromocriptine / Q000008:administration & dosage / Q000633:toxicity*; D003338:Corpus Luteum / Q000187:drug effects / Q000473:pathology; D004334:Drug Administration Schedule; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007247:Infertility, Female / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007564:Japan; D008136:Longevity / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010049:Ovarian Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010902:Pituitary Gland / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000978:Antiparkinson Agents; D018809:Proliferating Cell Nuclear Antigen; D001971:Bromocriptine