Pharmacokinetics and effects of 17β-estradiol and progesterone implants in ovariectomized rats
Pharmacokinetics and effects of 17β-estradiol and progesterone implants in ovariectomized rats
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DOI：
10.1016/j.jpain.2005.07.007
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发表时间：
2005-12-01
期刊：
影响因子：
4
通讯作者：
Quinones-Jenab, V
中科院分区：
文献类型：
--
作者：
Mannino, CA;South, SM;Quinones-Jenab, V
为了评价硅橡胶胶囊的药代动力学，卵巢切除（OVX）大鼠皮下植入含有17 β-雌二醇（5、10、15或20%胆固醇，其中5% 17 β-雌二醇等于0.4 mg）或孕酮（20、40、110或220 mg结晶孕酮）的该剂型。在OVX大鼠中，从这些胶囊释放的血清17 β-雌二醇和孕酮的时间过程的特征在于血清激素水平最初升高，随后下降，然后在植入后7 - 24天保持明显的稳态。两种激素的清除率都很高（17 β-雌二醇的总清除率为97.7 L/天，孕酮为20.9 L/天）。仅对于17 β-雌二醇和孕酮，在24天后从植入物释放11%的剂量。因此，硅橡胶膜代表了这些激素的速率控制屏障。17 β-雌二醇或孕酮的分级剂量与血清浓度之间呈线性关系。无论是在48，52.5，和55摄氏度测量的甩尾lasting，也不是吗啡的镇痛效力（ED 50值）的改变，通过连续给药的17 β-雌二醇或孕酮的分级剂量的稳态。我们演示了如何17 β-雌二醇或孕酮的一些行为效应的剂量依赖性分析可以进行稳态血清hormone concentration.Perspective：我们描述了一种方法，以获得持续的血清水平的雌激素或孕酮和这些持续的激素水平的后果对急性热伤害性和镇痛反应吗啡。这种激素替代的大鼠模型可以提供这些激素在病理性疼痛状态中的作用的见解。
For the pharmacokinetic evaluation of Silastic capsules, ovariectornized (OVX) rats were implanted subcutaneously with this dosage form containing 17 beta-estradiol (5, 10, 15, or 20% in cholesterol, where 5% 17 beta-estradiol equals 0.4 mg) or progesterone (20, 40, 110, or 220 mg of crystalline progesterone). The time-course of serum 17 beta-estradiol and progesterone released from these capsules in the OVX rat is characterized by an initial increase in serum hormone levels followed by a decline and then an apparent steady-state that persists from 7 to 24 days postimplant. Both hormones have large clearance values (total clearance is 97.7 L/day for 17 beta-estradiol and 20.9 L/clay for progesterone). For 17 beta-estradiol and progesterone only, 11% of the dose was released from the implant after 24 days. Thus, the Silastic membrane represents the rate controlling barrier for these hormones. The relationship between graded doses of 17 beta-estradiol or progesterone and serum concentration was linear. Neither tail flick latencies measured at 48, 52.5, and 55 degrees C nor the antinociceptive potency of morphine (ED50 values) were altered by continuous administration to steady-state of graded doses of 17 beta-estradiol or progesterone. We demonstrate how a dose-dependent analysis of some of the behavioral effects of 17 beta-estradiol or progesterone can be conducted at steady-state serum hormone concentrations.Perspective: we describe a method to obtain sustained serum levels of estrogen or progesterone and the consequences of these sustained hormone levels on acute thermal nociception and the antinociceptive response to morphine. This rat model of hormone replacement may provide insights into the role of these hormones in pathological pain states.