Dong Lei-Chi, Zhang Xiao-Hong, Ma Jiang, Luo Na, Song Wei, Li Ping, Li Hui-Jun
State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
J Ethnopharmacol. 2014 Nov 18;157:69-78. doi: 10.1016/j.jep.2014.09.021. Epub 2014 Sep 23.
Rhododendri Mollis Flos (RMF), termed as Naoyanghua in Chinese, is a traditional anti-rheumatoid arthritis and bruises herb with associated cardiotoxicity. The predominant rhodojaponins occurring in RMF are responsible for its efficacy and toxicity. The narrow therapeutic window of rhodojaponins necessitates monitoring the pharmacokinetics and pharmacodynamics so as to ensure the safety in practical applications of RMF.
Fifty-four male Sprague-Dawley rats were divided into a control group, a low-dose group and a high-dose group. After oral administration of RMF extract, the cardiotoxicity of RMF was evaluated by assessing ventricular function and by measuring the plasma levels of LDH, CK-MB and AST. Then, an LC-MS method was established to determine the rat plasma concentrations of three major rhodojaponins including rhodojaponin I, II and III (R-I, II and III) and was applied to pharmacokinetic study. Finally, based on an AUC-weighting approach, the integrated pharmacokinetics of three rhodojaponins was determined.
Compared with control group, cardiotoxicity was observed in RMF-treated rats with left ventricular dysfunction and with the continuously increased levels of LDH and CK-MB in a dose-dependent manner. The pharmacokinetic parameters (AUC0-t, AUC0-∞, t1/2, Tmax and Cmax) for R-I, II and III were markedly different, and the integrated pharmacokinetics was therefore converted to describe the holistic pharmacokinetic profiles of R-I, II and III, which correlated pretty well with cardiotoxicity.
It was found that myocardial damage was elicited by RMF extract in a dose-dependent manner and the plasma levels of LDH and CK-MB could reveal the severity of myocardial injury as potential markers. This study also highlighted the potential of integrated pharmacokinetics to provid a more comprehensive understanding of the relationship between the pharmacokinetic behaviors of traditional Chinese herbal medicine and its efficacy.
羊踯躅花（RMF），中药名为闹羊花，是一种传统的抗类风湿性关节炎和跌打损伤草药，但具有心脏毒性。RMF中主要的杜鹃素类化合物决定了其功效和毒性。杜鹃素类化合物狭窄的治疗窗使得有必要监测其药代动力学和药效学，以确保RMF在实际应用中的安全性。
将54只雄性Sprague-Dawley大鼠分为对照组、低剂量组和高剂量组。口服RMF提取物后，通过评估心室功能以及测量血浆中乳酸脱氢酶（LDH）、肌酸激酶同工酶（CK-MB）和天门冬氨酸氨基转移酶（AST）的水平来评价RMF的心脏毒性。然后，建立液相色谱-质谱（LC-MS）法测定大鼠血浆中三种主要杜鹃素类化合物（杜鹃素I、II和III，即R-I、II和III）的浓度，并将其应用于药代动力学研究。最后，基于曲线下面积（AUC）加权法，确定三种杜鹃素类化合物的整合药代动力学。
与对照组相比，接受RMF治疗的大鼠出现心脏毒性，表现为左心室功能障碍，且LDH和CK-MB水平呈剂量依赖性持续升高。R-I、II和III的药代动力学参数（AUC0-t、AUC0-∞、t1/2、Tmax和Cmax）有显著差异，因此将整合药代动力学转换以描述R-I、II和III的整体药代动力学特征，其与心脏毒性相关性良好。
发现RMF提取物可引起剂量依赖性心肌损伤，血浆中LDH和CK-MB水平可作为潜在标志物揭示心肌损伤的严重程度。本研究还强调了整合药代动力学在更全面理解中药药代动力学行为与其功效之间关系方面的潜力。
