Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats
Pharmacokinetic and pharmacodynamic profiles of the novel serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized Sprague-Dawley rats
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DOI：
10.1016/j.brainres.2006.04.057
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发表时间：
2006-07-07
期刊：
影响因子：
2.9
通讯作者：
Deecher, Darlene C.
中科院分区：
文献类型：
--
作者：
Alfinito, Peter D.;Huselton, Christine;Deecher, Darlene C.
琥珀酸去甲文拉法辛（DVS）是一种新型5-羟色胺（5-HT）和去甲肾上腺素（NE）再摄取抑制剂（SNRI），目前正处于临床开发阶段，用于治疗重度抑郁症和更年期相关的血管紧张症状。既往研究记录了DVS在雄性大鼠中的药代动力学和药效学特征。然而，类似的研究还没有在卵巢切除（OVX）大鼠中进行，OVX是一种模拟绝经期卵巢激素丢失的模型。因此，本研究的目的是表征DVS在OVX大鼠中的药代动力学和药效学特性。在DVS给药（30 mg/kg，口服）后30 min，血浆、脑（总脑减去下丘脑）和下丘脑中的去甲文拉法辛水平分别达到峰值，浓度为7.0、10.8和9.5 μ M（假设1 g = 1 ml）。去甲文拉法辛在血浆、脑和下丘脑中的表观终末半衰期分别为3.0、2.1和2.5 h。基于AUC（O-last），脑/血浆和下丘脑/血浆比值分别为1.7和1.3。下丘脑视前内侧区微透析实验表明，DVS（30 mg/kg，s.c.），在WAY-10063 S（S-HT 1A拮抗剂）存在下，给药后1小时5-HT水平增加225%。去甲肾上腺素水平在给药后3小时增加44%，而多巴胺水平不变。因此，在OVX大鼠中，DVS具有良好的药代动力学特性，快速的脑渗透性，优异的脑渗透性，并选择性地增加下丘脑中的5-HT和NE水平。这项工作支持的概念，DVS可能有效用，用于治疗更年期妇女的疾病，其中5-HT和/或NE的变化已经牵连。(c)2006 Elsevier B. V.保留所有权利。
Desvenlafaxine succinate (DVS) is a novel serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) that is currently in clinical development for the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Previous studies have documented the pharmacokinetic and pharmacodynamic profiles of DVS in male rats. Similar studies, however, have not been performed in ovariectomized (OVX) rats, a model that mimics the loss of ovarian hormones that occurs at menopause. The goal of the present study, therefore, was to characterize the pharmacokinetic and pharmacodynamic properties of DVS in OVX rats. Desvenlafaxine levels peaked in plasma, brain (total brain minus hypothalamus) and hypothalamus at concentrations of 7.0, 10.8 and 9.5 mu M (assuming 1 g = 1 ml), respectively, 30 min post-dosing DVS (30 mg/kg, oral). The apparent terminal half-lives of desvenlafaxine in plasma, brain and hypothalamus were 3.0, 2.1 and 2.5 h, respectively. Based on AUC(O-last), brain to plasma and hypothalamus to plasma ratios were 1.7 and 1.3, respectively. Microdialysis experiments in the medial preoptic area of the hypothalamus showed that DVS (30 mg/kg, s.c.), in the presence of WAY-10063S (S-HT1A antagonist), increased 5-HT levels 225% at 1 h post-dosing. Norepinephrine levels increased 44% at 3 h post-dosing while dopamine levels were unchanged. Thus, in OVX rats, DVS has good pharmacokinetic properties, rapid brain penetration, excellent brain penetrability and selectively increases 5-HT and NE levels in the hypothalamus. This work supports the notion that DVS could have utility for treating disorders in menopausal women in which changes in 5-HT and/or NE have been implicated. (c) 2006 Elsevier B.V. All rights reserved.