Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, No. 155 Hanzhong Road, Nanjing 210029, China.
J Ethnopharmacol. 2012 Oct 31;144(1):195-200. doi: 10.1016/j.jep.2012.09.005. Epub 2012 Sep 13.
Celastrol is a natural compound extracted from the traditional Chinese medicinal herb, Thunder God Vine (TGV). Owing to its potential anti-inflammatory and antitumor effects, celastrol has been considered as a promising candidate for drug development.
To establish a sensitive LC-MS/MS method to investigate the pharmacokinetic properties of celastrol in rats. Key pharmacokinetic issues of celastrol including oral bioavailability, comparative pharmacokinetics between pure compound and tablet preparation, as well as gender-related pharmacokinetic difference are to be addressed for the first time.
Sprague-Dawley rats were administrated an intravenous dose (100 μg kg(-1)) of pure celastrol and an oral dose (1000 μg kg(-1)) of pure celastrol and TGV tablets (corresponding to 534 μg kg(-1) of celastrol), respectively. At different time points, the concentration of celastrol in rat plasma was determined by a sensitive and well-validated LC-MS/MS method. Main pharmacokinetic parameters including area under the plasma concentration-time curve (AUC), maximal plasma concentration (Cmax), the time for maximal concentration (Tmax) and mean residence time (MRT) were estimated by Drug and Statistic1.0 pharmacokinetic software (Chinese Pharmacological Association, Anhui, PR China). Statistical analysis was performed using two one-side t test with p-values less than 0.05 as the level of significance.
The standard curve of celastrol showed good linearity in the concentration range of 0.11~54.3 ng mL(-1) in our current method, with acceptable selectivity, precision, recovery, and stability. The oral absolute bioavailability of celastrol significantly increased from 17.06% for pure celastrol to 94.19% for TGV tablets containing equivalent celastrol. After oral administration of TGV tablets, the Cmax and AUC values of celastrol in female rats were (32.03±8.41) μg L(-1) and (379.49±118.19) μg h L(-1), which were significantly higher (p<0.01) than that in males with the values of (14.31±7.33) μg L(-1) and (188.17±92.33) μg h L(-1).
Celastrol administered orally in the rat was poorly absorbed into the systemic circulation. However, the poor absorption of celastrol could be greatly improved when celastrol-containing TGV tablets orally administered, and thereby the oral bioavailability of celastrol was significantly increased. As for gender difference, female rats showed significantly better absorption of celastrol than males.
从雷公藤中提取的天然化合物雷公藤红素具有潜在的抗炎和抗肿瘤作用，被认为是药物开发的有前途的候选物。
建立灵敏的 LC-MS/MS 方法来研究大鼠体内的雷公藤红素药代动力学特性。首次解决了雷公藤红素的关键药代动力学问题，包括口服生物利用度、纯化合物与片剂制剂之间的比较药代动力学以及与性别相关的药代动力学差异。
给予 Sprague-Dawley 大鼠静脉内剂量（100μg/kg）的纯雷公藤红素和口服剂量（1000μg/kg）的纯雷公藤红素和雷公藤红素片剂（相当于 534μg/kg 的雷公藤红素）。在不同时间点，通过灵敏且经过良好验证的 LC-MS/MS 方法测定大鼠血浆中雷公藤红素的浓度。通过 Drug and Statistic1.0 药代动力学软件（中国药理学会，安徽，中国）估算主要药代动力学参数，包括曲线下血浆浓度-时间面积（AUC）、最大血浆浓度（Cmax）、最大浓度时间（Tmax）和平均驻留时间（MRT）。使用双单侧 t 检验进行统计分析，p 值<0.05 为显著性水平。
本研究中，雷公藤红素的标准曲线在 0.11~54.3ng/mL 的浓度范围内表现出良好的线性，具有可接受的选择性、精密度、回收率和稳定性。纯雷公藤红素的口服绝对生物利用度从 17.06%显著增加到含有等效雷公藤红素的雷公藤红素片剂的 94.19%。口服雷公藤红素片剂后，雌性大鼠的 Cmax 和 AUC 值分别为（32.03±8.41）μg/L 和（379.49±118.19）μg·h/L，明显高于雄性大鼠的（14.31±7.33）μg/L 和（188.17±92.33）μg·h/L（p<0.01）。
大鼠口服给予的雷公藤红素吸收到体循环中较差。然而，当口服给予含有雷公藤红素的雷公藤红素片剂时，雷公藤红素的吸收可以得到极大改善，从而使雷公藤红素的口服生物利用度显著提高。关于性别差异，雌性大鼠对雷公藤红素的吸收明显优于雄性大鼠。
