Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR-623, a Novel Liver X-Receptor Agonist, in Healthy Participants
Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR-623, a Novel Liver X-Receptor Agonist, in Healthy Participants
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DOI：
10.1177/0091270009335768
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发表时间：
2009-06-01
影响因子：
2.9
通讯作者：
Meng, Xu
中科院分区：
文献类型：
--
作者：
Katz, Arie;Udata, Chandrasekhar;Meng, Xu
肝x受体（LXR）激动剂被认为可以增强逆向胆固醇转运（RCT），这一过程被认为是将胆固醇从外周转运回肝脏。因此，通过上调胆固醇转运体（如三磷酸腺苷结合盒ABCA1和ABCG1）来增强RCT可以抑制动脉粥样硬化的进展。LXR-623是LXRs α和β的合成配体，在动脉粥样硬化动物模型中显示出前景。作者介绍了LXR-623在健康参与者中的安全性、药代动力学和药效学的单次递增剂量研究结果。LXR-623吸收迅速，约2小时达到峰值浓度（C-max）。C-max和浓度-时间曲线下面积呈剂量正比增加。平均终末处置半衰期在41 ~ 43小时之间，与剂量无关。LXR激活导致ABCA1和ABCG1表达呈剂量依赖性增加。通过群体药代动力学分析进一步表征LXR-623浓度对ABCA1和ABCG1表达的影响，EC50估计分别为526 ng/mL和729 ng/mL。在测试的2个最高剂量中观察到中枢神经系统相关不良事件。本文所描述的药效学效应是LXR激动剂首次在人体中实现“靶标结合”。
Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C-max) achieved at approximately 2 hours. The C-max and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC50 estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.