Pharmacokinetic study of triptolide, a constituent of immunosuppressive chinese herb medicine, in rats
Pharmacokinetic study of triptolide, a constituent of immunosuppressive chinese herb medicine, in rats
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DOI：
10.1248/bpb.30.702
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发表时间：
2007-04-01
影响因子：
2
通讯作者：
A, Jiye
中科院分区：
文献类型：
--
作者：
Shao, Feng;Wang, Guangji;A, Jiye
雷公藤甲素是一种潜在的抗免疫药物，具有多有机毒性，但其毒性机制尚未明确。本文旨在研究雷公藤甲素在大鼠体内的药动学特征，为探讨雷公藤甲素的毒性机制提供线索。研究雄性Sprague-Dowley大鼠单次口服和静脉给药后雷公藤甲素的吸收、分布、代谢和排泄情况。口服0.6、1.2和2.4 mg/kg后，雷公藤甲素血药浓度在15 min内达到最大值，随后迅速下降，消除半衰期从16.81 min降至21.70 min。静脉给药后雷公藤甲素动力学符合单室模型。在0.6 mg/kg剂量下，口服绝对生物利用度为72.08%。雷公藤甲素也在所有选定的组织中迅速分布和消除。在48 h内，该剂量的雷公藤甲素作为母体药物从胆汁、尿液或粪便中被回收的不到1%，而在给药后4 h，组织和血浆中已检测不到雷公藤甲素，而C组（口服：1.2 mg/kg）和D组（口服：2.4 mg/kg）对雷公藤甲素表现出明显的毒性反应，部分大鼠甚至死亡。结果表明，雷公藤甲素代谢广泛，消除迅速，毒性作用滞后于暴露浓度。
Triptolide is a potential anti-immune agent, and has shown multi-organic toxicity, however its toxic mechanism remained undiscovered. This paper aimed at characterizing the pharmacokinetic profiles of triptolide in rats to provide the clue to approach the toxic mechanism. The absorption, distribution, metabolism and excretion of triptolide were investigated in male Sprague-Dowley rats after single doses of oral and i.v. administration. After oral administration of 0.6, 1.2 and 2.4 mg/kg, the concentration of triptolide in plasma reached the maximum within 15 min, and declined rapidly with an elimination half-life from 16.81 to 21.70 min. The triptolide kinetics was fitted into one-compartment model after i.v. administration. Oral absolute bioavailability was 72.08% at the dose of 0.6 mg/kg. Triptolide was also rapidly distributed and eliminated in all selected tissues. Less than 1% triptolide of the dose was recovered from the bile, urine or feces as parent drug within 48 h. While triptolide could not be detected in tissues and plasma at 4 h post dose, rats in the group C (oral: 1.2 mg/kg) and D (oral: 2.4 mg/kg) showed obvious toxic response to triptolide and some of rats even died out. It was indicated that triptolide was metabolized extensively, eliminated rapidly, and also showed that the toxicity produced by the triptolide was lag behind the exposure concentration.