Songvut Phanit, Chariyavilaskul Pajaree, Tantisira Mayuree H, Khemawoot Phisit
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Planta Med. 2019 Apr;85(6):483-490. doi: 10.1055/a-0835-6671. Epub 2019 Jan 30.
The aim of this study was to investigate the safety and pharmacokinetic profiles of a newly developed, standardized extract of (ECa 233) capsule in healthy Thai volunteers. This study was designed as an open-labeled, 2-sequence dosage, single- and repeated-dose study investigated under fasting conditions. Plasma concentrations of the parent compounds and their relative acid metabolites were measured and pharmacokinetic parameters were calculated using noncompartmental analysis. Tolerability was assessed based on physical examinations, monitoring of vital signs, clinical laboratory tests, and any observed adverse events. A key finding of this study was that the pharmacokinetics of ECa 233 in healthy volunteers did not correspond with its pharmacokinetics in animal studies. As indicated in human pharmacokinetic parameters, maximum plasma concentration and area under the curve of the parent compounds (madecassoside and asiaticoside) were very low, while their respective metabolites (madecassic acid and asiatic acid) demonstrated higher values. Based on the pharmacokinetic results observed in the dose comparison, accumulation of active metabolites after repeated dose is highly suggestive. In addition, the asiatic acid profile showed 2-fold increase in C and AUC after increasing dose from 250 to 500 mg of ECa 233. Lastly, the safety and tolerability evaluation illustrated that single and multiple doses in both 250 and 500 mg oral administration of ECa 233 were well tolerated, and none of the volunteers discontinued their participation due to adverse effects during the study.
本研究旨在调查一种新开发的标准化（ECa 233）胶囊提取物在健康泰国志愿者中的安全性和药代动力学特征。本研究设计为开放标签、2序列剂量、单剂量和重复剂量研究，在禁食条件下进行。测量母体化合物及其相关酸性代谢物的血浆浓度，并使用非房室分析计算药代动力学参数。根据体格检查、生命体征监测、临床实验室检查以及任何观察到的不良事件评估耐受性。本研究的一个关键发现是，ECa 233在健康志愿者中的药代动力学与其在动物研究中的药代动力学不相符。从人体药代动力学参数来看，母体化合物（羟基积雪草苷和积雪草苷）的最大血浆浓度和曲线下面积非常低，而它们各自的代谢物（羟基积雪草酸和积雪草酸）显示出较高的值。基于剂量比较中观察到的药代动力学结果，重复给药后活性代谢物的积累具有高度提示性。此外，将ECa 233的剂量从250毫克增加到500毫克后，积雪草酸的血药浓度-时间曲线下面积（AUC）增加了2倍。最后，安全性和耐受性评估表明，口服250毫克和500毫克ECa 233的单剂量和多剂量均耐受性良好，在研究期间没有志愿者因不良反应而停止参与。
