title: Collaborative work on evaluation of ovarian toxicity. 8) Two- or four-week repeated-dose studies and fertility study of Anastrozole in female rats.
abstract: The main focus of this study was to determine the optimal administration period in terms of toxic effects on ovarian morphological changes. To assess the morphological and functional changes induced by anastrozole in ovaries, the compound was administered to female rats at dose levels or 0, 0.01, 0.1 and 50 mg/kg for 2 or 4 weeks in the repeated dose toxicity study and at levels of 0, 0.01, 0.1 and 5 mg/kg from 2 weeks prior to mating to Day 7 or pregnancy in the female fertility study. In the repeated dose toxicity study, large abnormal atretic follicles, follicular cysts, a decrease in corpus luteum and depletion of developing corpus luteum were observed in the 1 and/or 50 mg/kg groups of both the 2-week and 4-week studies in a histopathological examination of the ovaries. In the female fertility study, the pregnancy rate was decreased in the 5 mg/kg group. Irregular estrous cycles, such as an extended cycle or no cycle, were observed in the 0.1 and 5 mg/kg groups. At necropsy, decreased numbers of implantations, corpora lutea and live fetuses were noted in the 1 and/or 5 mg/kg groups. Based on these findings, histopathological changes in the ovary are important endpoints for the evaluation of drugs inducing ovarian damage. We conclude that a 2-week administration period is sufficient to detect ovarian toxicity of anastrozole in a repeated dose toxicity study.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi-Sankyo Co., Ltd., Fukuroi-shi, Shizuoka, Japan. shirai.makoto.v7@daiichisankyo.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Shirai
authors.forename: Ken
authors.initials: K
authors.lastname: Sakurai
authors.forename: Wataru
authors.initials: W
authors.lastname: Saitoh
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Munehiro
authors.initials: M
authors.lastname: Teranishi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Furukawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
authors.forename: Sunao
authors.initials: S
authors.lastname: Manabe
mesh_terms: D000077384:Anastrozole; D000818:Animals; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; 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*; D007564:Japan; D008297:Male; D009570:Nitriles / Q000008:administration & dosage / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D055818:Public-Private Sector Partnerships; D051381:Rats; D011916:Rats, Inbred F344; D012958:Societies, Scientific; D013047:Specific Pathogen-Free Organisms; D018675:Toxicity Tests / Q000379:methods*; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*; D014599:Uterus / Q000187:drug effects / Q000473:pathology
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole