Key Lab of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing 100850, PR China.
J Ethnopharmacol. 2013 Oct 28;150(1):131-7. doi: 10.1016/j.jep.2013.08.018. Epub 2013 Aug 29.
Tripterygium wilfordii HOOK F (TWHF) is a traditional Chinese medicine used in the treatment of various autoimmune diseases and inflammatory disorders including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and skin diseases. Triptolide (TP) is one of the main active ingredients of this traditional Chinese medicine. MC002 is a novel semi-synthetic derivate of TP which is highly water soluble, acts as a prodrug and is converted to TP in vivo.
A sensitive, rapid method for the simultaneous determination of TP and its chemo-unstable prodrug MC002 in dog blood was developed and validated using electrospray ionization (ESI) liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using this method, a pharmacokinetic study of MC002 and TP following an intravenous drip infusion of 0.2mg/kg MC002 in dogs was performed.
Chemo-degradation of the prodrug in blood samples was inhibited by the addition of a small amount of sodium fluoride solution before using liquid-liquid extraction with ethyl acetate. The concentrations of MC002 and TP in dog blood were determined using the LC-MS/MS method.
The quantitative method showed good precision and stability and is suitable for the assay of biological samples. The pharmacokinetic study showed that the elimination of MC002 was faster than that of TP, and the concentrations and AUC0-t values of TP were higher than MC002. MC002 can rapidly convert to TP in vivo.
This validated method was successfully applied in a pharmacokinetic study of MC002 following an intravenous drip infusion in dogs. With the development of this new prodrug of TP as a promising anti-cancer drug, this method is suitable for its further analysis in clinical studies.
雷公藤（TWHF）是一种传统中药，用于治疗各种自身免疫性疾病和炎症性疾病，包括类风湿关节炎（RA）、系统性红斑狼疮（SLE）和皮肤病。雷公藤内酯醇（TP）是这种中药的主要活性成分之一。MC002 是 TP 的一种新型半合成衍生物，具有高水溶性，作为前药，在体内转化为 TP。
建立并验证了一种灵敏、快速的同时测定犬血中 TP 和其化学不稳定前药 MC002 的方法，采用电喷雾电离（ESI）液相色谱-串联质谱（LC-MS/MS）法。采用该方法，对犬静脉滴注 0.2mg/kg MC002 后 MC002 和 TP 的药代动力学进行了研究。
在使用乙酸乙酯液-液萃取前，在血液样品中加入少量氟化钠溶液以抑制前药的化学降解。采用 LC-MS/MS 法测定犬血中 MC002 和 TP 的浓度。
定量方法具有良好的精密度和稳定性，适用于生物样品的测定。药代动力学研究表明，MC002 的消除速度快于 TP，TP 的浓度和 AUC0-t 值高于 MC002。MC002 可在体内迅速转化为 TP。
该验证方法成功应用于犬静脉滴注 MC002 后的药代动力学研究。随着 TP 这种新型前药作为有前途的抗癌药物的发展，该方法适用于其在临床研究中的进一步分析。
