Treinen K A, Rehm S, Wier P J
Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Toxicol Sci. 1998 Feb;41(2):199-207. doi: 10.1006/toxs.1997.2404.
Idoxifene, a tissue-specific selective estrogen receptor modulator, was evaluated in male and female rats and female rabbits after oral administration for effects on fertility and/or embryo-fetal development. In all studies, adult toxicity was evident at doses >/=0.03 mg/kg/day in rats and >/=0.1 mg/kg/day in rabbits as evidenced by decreased body weight and/or food consumption. In the male fertility study, rats were treated with 0.003, 0.3, or 3.0 mg/kg/day for 64 to 68 days. Doses >/=0.3 mg/kg/day decreased seminal vesicle and prostate weights and impaired posttesticular sperm development, resulting in decreased epididymal sperm count and weight, but did not affect male fertility. In the female fertility study, rats were treated for 2 weeks prior to mating until insemination with 0.003, 0.03, or 3.0 mg/kg/day. Disrupted estrous cycles, impaired fertility, increased preimplantation loss, and increased vaginal fluid at necropsy were evident at >/=0.03 mg/kg/day. In the early embryonic development study, pregnant female rats were treated from days 0 to 6 postcoitus (pc) with 0.003, 0.03, or 3.0 mg/kg/day idoxifene. Partial or complete preimplantation loss was seen at 0.03 and 3.0 mg/kg/day, respectively. In the embryo-fetal development study, pregnant rats were treated from days 6 to 17 pc with 0.003, 0.03, or 3.0 mg/kg/day. At 3.0 mg/kg/day there was maternal lethality, excess vaginal fluid, embryo-fetal death, generalized fetal edema, and developmental delays. Excess vaginal fluid but no fetal effects were seen at 0.03 mg/kg/day. There were no treatment-related effects at 0.003 mg/kg/day in any rat reproduction study performed. In the rabbit embryo-fetal development study, pregnant New Zealand White rabbits were treated from days 6 to 20 pc with 0.01, 0.1, or 1.0 mg/kg/day idoxifene. At 1.0 mg/kg/day there was maternal lethality, vaginal or uterine bleeding, abortion/premature deliveries, and embryolethality. Vaginal or uterine bleeding was seen at 0.1 mg/kg/day. No treatment-related effects were observed at 0.01 mg/kg/day. Although systemic toxicity was evident in all the studies, the effects of idoxifene on rat and rabbit reproduction were considered to be due to the pharmacological activity of the compound.
依多昔芬是一种组织特异性选择性雌激素受体调节剂，对雄性和雌性大鼠以及雌性家兔进行了口服给药，以评估其对生育力和/或胚胎-胎儿发育的影响。在所有研究中，大鼠剂量≥0.03mg/kg/天、家兔剂量≥0.1mg/kg/天时出现明显的成年毒性，表现为体重减轻和/或食物摄入量减少。在雄性生育力研究中，大鼠分别接受0.003、0.3或3.0mg/kg/天的治疗，持续64至68天。剂量≥0.3mg/kg/天时，精囊和前列腺重量减轻，睾丸后精子发育受损，导致附睾精子数量和重量减少，但不影响雄性生育力。在雌性生育力研究中，大鼠在交配前2周直至授精期间接受0.003、0.03或3.0mg/kg/天的治疗。剂量≥0.03mg/kg/天时，发情周期紊乱、生育力受损、着床前损失增加以及尸检时阴道分泌物增多。在早期胚胎发育研究中，怀孕雌性大鼠在交配后第0至6天接受0.003、0.03或3.0mg/kg/天的依多昔芬治疗。分别在0.03和3.0mg/kg/天时观察到部分或完全着床前损失。在胚胎-胎儿发育研究中，怀孕大鼠在交配后第6至17天接受0.003、0.03或3.0mg/kg/天的治疗。在3.0mg/kg/天时，出现母体死亡、过多阴道分泌物、胚胎-胎儿死亡、全身性胎儿水肿和发育迟缓。在0.03mg/kg/天时观察到过多阴道分泌物，但未对胎儿产生影响。在任何大鼠生殖研究中，0.003mg/kg/天的剂量均未产生与治疗相关的影响。在家兔胚胎-胎儿发育研究中，怀孕的新西兰白兔在交配后第6至20天接受0.01、0.1或1.0mg/kg/天的依多昔芬治疗。在1.0mg/kg/天时，出现母体死亡、阴道或子宫出血、流产/早产以及胚胎死亡。在0.1mg/kg/天时观察到阴道或子宫出血。在0.01mg/kg/天时未观察到与治疗相关的影响。尽管在所有研究中均出现了全身毒性，但依多昔芬对大鼠和家兔生殖的影响被认为是由于该化合物的药理活性所致。
