Effects of repeated doses of compound E for 4 and 9 weeks on the male reproductive organs.
Results of two toxicity studies of Compound E, which is an anticancer drug, on male reproductive organs and fertility by oral repeated dosing at dose levels of 12.5, 25 and 50 mg/kg/day for 4 and 9 weeks in rats were compared. After repeated dosing, the male fertility was studied by mating with untreated female animals. At the dose of 50 mg/kg/day in the 4-week study, Compound E significantly decreased testes weight and number of epididymal sperm, caused histopathological changes in the testis and epididymis characterized by decreased germ cells, but did not affect fertility. The dose of 25 mg/kg/day in the 9-week study caused reduction in epididymal weight and number of epididymal sperm and histopathological changes in the testis. The dose of 50 mg/kg/day in the 9-week study was lethal and caused more prominent toxic effects in the reproductive organs and loss of fertility. The present studies suggest that the order of sensitivity of parameters on male reproductive organs is as follows; histopathological examination = organ weight > number of sperm in epididymis > pregnancy index> copulation index. Further, 4-weeks repeated dosing is of sufficient duration to predict adverse effects of test compounds.
Okada
F
F
Department of Drug Safety Research, Eisai Co., Ltd., Gifu, Japan.
Niwa
N
N
Hosokawa
S
S
Kawaguchi
T
T
Okuda
Y
Y
Matsubara
Y
Y
Yamatsu
K
K
Igarashi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002585:Cesarean Section; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005298:Fertility / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage / Q000633:toxicity*; D013737:Testis / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D013449:Sulfonamides