Collaborative work on evaluation of ovarian toxicity. 7) Effects of 2- or 4- week repeated dose studies and fertility study of cyclophosphamide in female rats.
The main focus of this study was to determine the optimal administration period concerning the toxic effects on ovarian morphological changes in the repeated dose toxicity study. In order to assess the morphological and functional changes induced in the ovary by cyclophosphamide (CP), the compound was administrated to female rats at dose levels of 0, 5, 10 and 20 mg/kg for the repeated dose toxicity study for 2 or 4 weeks, and at 0, 5, 10, and 20 mg/kg for the female fertility study from 2 weeks prior to mating to Day 7 of pregnancy. In the repeated dose toxicity study, increases in large sized atretic follicles, atrophy of corpora lutea were observed in the 20 mg/kg group in the 4-week study by the histopathological examination of the ovaries. There were no drug-related changes in the ovary in the 2-week study. In the female fertility study, the numbers of implantation were slightly decreased and the corpora lutea of pregnancy was not observed in the 20 mg/kg group. The dose-dependent increase in the incidence of post-implantation loss was observed, and no abnormalities were observed in the estrus cycle and mating in all treated groups. From these findings, the histopathological changes in the ovary are important endpoints for the evaluation of drug-induced ovarian damage as well as caesarean section. In conclusion, a 4-week administration period is sufficient to detect the ovarian toxicity of CP in the repeated dose toxicity study.
Sato
Makoto
M
Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. m_sato@research.otsuka.co.jp
Shiozawa
Kei
K
Uesugi
Toru
T
Hiromatsu
Riki
R
Fukuda
Meiko
M
Kitaura
Keisuke
K
Minami
Takanori
T
Matsumoto
Satoshi
S
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D010064:Embryo Implantation / Q000187:drug effects; D020964:Embryo Loss / Q000139:chemically induced; D004622:Embryo, Mammalian / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D007564:Japan; D008297:Male; 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; D018675:Toxicity Tests / Q000379:methods*; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000473:pathology
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide