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首页> 外文期刊>Reproductive toxicology >Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits.
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Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits.

机译：依西美坦（一种抗肿瘤芳香化酶灭活剂）对大鼠和兔子的生殖毒性。

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摘要

Exemestane is an orally active, irreversible inactivator of aromatase, structurally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausal women. The reproductive and developmental toxicity of exemestane was assessed in rats and rabbits with oral administration. Pivotal experiments included a fertility study (Segment I), in which female rats received exemestane doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (cesarean-sectioned dams), or until GD 15 and then from D 1 to D 21 postpartum (dams allowed to deliver), and developmental toxicity studies (Segment II), in which rats and rabbits were treated from GD 6 through GD 17 (rats) or GD 18 (rabbits) at doses of 10, 50, 250, or 810 mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were cesarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-third of the rats was allowed to litter and rear pups to weaning. No pivotal male fertility or peri- and postnatal studies were performed, taking into consideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams allowed to deliver. Their F1 offspring were raised to adulthood, when they were evaluated for reproductive performance, and the F1 females were terminated on GD 20. The dosing schedule for the Segment I study in rats, which included a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of parturition). This withdrawal of treatment was put in place because in a preliminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition.Overall, studies in rats showed that female fertility was not affected up to 100 mg/kg/day, but doses higher than 4 mg/kg/day, which is approximately the pharmacologically active dose (ED50 = 3.7 mg/kg), prolonged gestation and impaired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in resorptions at doses higher than 10 mg/kg/day, a reduction in fetal body weights at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (developmental toxicity study), and an increase in placental weights at all doses. Female fetuses exposed in utero until GD 20 at 100 mg/kg/day showed an increase in the anogenital distance, very likely related to an increase of the potent androgen DHT as a consequence of aromatase inhibition. Morphologic examinations in fetuses and born pups that were exposed in utero up to the end of the organogenesis period, as well as postnatal investigations on offspring up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal food intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetuses, but did not affect fetal morphology. It was concluded that exemestane did not affect parturition in rats at 4 mg/kg/day or pregnancy in rabbits at 90 mg/kg/day (about 1.5 and 70 times the human dose, respectively, on a mg/m2 basis) and was not teratogenic in rats and rabbits.Exemestane is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women.
机译：依西美坦是一种芳香酶的口服活性，不可逆失活剂，在结构上与天然底物雄烯二酮有关，临床上每天使用25 mg，用于治疗绝经后妇女的晚期乳腺癌。在大鼠和兔子口服时评估了依西美坦的生殖和发育毒性。关键的实验包括一项生育力研究（第I部分），其中雌性大鼠从胎膜早破的两周开始接受4、20或100 mg / kg / kg的依西美坦剂量，直到GD 20（剖宫产大坝），或者直到GD 15为止。从产后第1天到第21天（允许产水坝）和发育毒性研究（第II部分），其中大鼠和兔子从GD 6至GD 17（大鼠）或GD 18（兔）的剂量为10， 50、250或810 mg / kg /天和30、90或270 mg / kg /天。将所有兔子和三分之二的大鼠在妊娠快要结束时进行剖宫产，以确定产仔参数并检查胎儿的结构异常。其余的三分之一的大鼠被允许乱扔垃圾，并让幼崽断奶。考虑到治疗用途，未进行关键的男性生育力或围产期和产后研究。两项研究均在大鼠中评估了第一代后代对产后的影响，包括允许分娩的水坝部分。他们的F1后代长大后进入成年期，对其生殖能力进行评估，F1雌性在GD 20时终止。在大鼠中进行I段研究的给药方案（包括产后成分）被确定为排除暴露前和暴露后的剂量。分娩期间（通过退出GD 16治疗直至分娩结束）。之所以放弃治疗，是因为在一项包括围产期在内的初步研究中，剂量为5至200 mg / kg /天的剂量延长了妊娠并干扰了分娩。总体而言，在大鼠中进行的研究表明，女性的生育能力并未受到影响。至100 mg / kg /天，但剂量高于4 mg / kg /天，大约是药理活性剂量（ED50 = 3.7 mg / kg），延长的妊娠和分娩不良，导致产妇死亡和分娩死亡后代用GD 20杀死的大鼠在高于10 mg / kg /天的剂量下显示出与吸收无关的剂量增加，在20和100 mg / kg /天（生育力研究）和810 mg / kg /天的胎儿体重减少（发育毒性研究），并在所有剂量下均增加胎盘重量。在子宫内暴露直到100 mg / kg / day的GD 20的雌性胎儿的肛门生殖器距离增加，这很可能与芳香酶抑制作用导致雄激素DHT的增加有关。对胎儿和出生的幼仔进行形态学检查，直到子宫内直到器官发生期结束为止，以及对成年后代的产后调查均未发现与治疗相关的影响。在一项针对兔子的发育毒性研究中，以270 mg / kg /天的剂量治疗会影响孕妇的食物摄入和体重增加，导致约30％的怀孕女性流产或完全吸收，并减轻了体重和活胎的数量，但是不影响胎儿形态。得出的结论是，依西美坦对大鼠4 mg / kg / day的分娩或对兔子以90 mg / kg / day的妊娠（以mg / m2分别约为人剂量的1.5倍和70倍）不影响分娩，并且Exemestane仅在绝经后妇女中使用。它的标签包括在孕妇或哺乳期妇女中使用的禁忌症。

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