Kuhnz W, Putz B
Research Laboratories, Schering AG, Berlin, FRG.
Pharmacol Toxicol. 1989 Sep;65(3):217-22. doi: 10.1111/j.1600-0773.1989.tb01160.x.
Oestrogen concentrations (oestradiol = E2 and oestriol = E3) were determined in plasma and liver tissue of female rats before, during and after treatment with two different doses (1.2 and 12.0 mg/kg/d) of oestradiol valerate (E2-val) given in the feed over 27 days. The oral bioavailability of E2 was determined in a pharmacokinetic study in which rats received a single intramuscular administration of E2-val. The aim of the present investigation was to support the evaluation of the results of a previous 90 weeks chronic toxicity and tumorigenicity study in rats where the same dosages were administered. The bioavailability was approximately 0.5%; the systemic body burden of exogenous E2 was 1.6 fold, the endogenous E2 burden at the low, and 9 fold at the high dose. Despite these low values, distinct systemic effects were noted. At 1.2 mg/kg/d a marked decrease in food consumption and body weight gain occurred in the 27 day study as well as in the chronic study. In addition, in the latter study mortality increased from the low dose onwards and was complete at the high dose after 72 weeks. The incidence of pituitary adenoma increased. The results indicate that theoretically rats are far more sensitive towards exogenous oestradiol treatment than humans.
在雌性大鼠经口给予两种不同剂量（1.2和12.0毫克/千克/天）戊酸雌二醇（E2-val）持续27天的治疗前、治疗期间及治疗后，测定其血浆和肝脏组织中的雌激素浓度（雌二醇=E2，雌三醇=E3）。在一项药代动力学研究中，给大鼠单次肌肉注射E2-val，测定E2的口服生物利用度。本研究的目的是为之前对大鼠进行的为期90周的慢性毒性和致癌性研究结果评估提供支持，该研究采用了相同的给药剂量。生物利用度约为0.5%；外源性E2的全身负担在低剂量时是内源性E2负担的1.6倍，在高剂量时是9倍。尽管这些数值较低，但仍观察到明显的全身效应。在为期27天的研究以及慢性研究中，给予1.2毫克/千克/天的剂量时，食物摄入量和体重增加显著下降。此外，在后者的研究中，从低剂量开始死亡率增加，在高剂量时72周后全部死亡。垂体腺瘤的发生率增加。结果表明，理论上大鼠对外源性雌二醇治疗的敏感性远高于人类。
