Yu Jiaoyan, Zhang Ruitao, Zhang Tian, Zhao Jun, Zhang Yang, Wang Qingwei, Liu Linna, Xu Yuan, Shi Lei
Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China.
Biomed Chromatogr. 2020 Jul;34(7):e4837. doi: 10.1002/bmc.4837. Epub 2020 Apr 17.
The objective of traditional Chinese medicine (TCM) combination theory is to "reduce toxicity and increase efficiency", especially to solve the liver toxicity of many TCMs. Fructus Meliae Toosendan (CLZ)-Fructus Foeniculi (XHX) is a typical traditional Chinese herb pair that decreases the toxicity and increases the efficiency of the herbs. Fructus Meliae Toosendan (CLZ, cold-natured) has significant liver toxicity. However, it has been widely used in combination with Fructus Foeniculi (XHX, hot-natured) for thousands of years in TCM, in which form it shows no hepatotoxicity, indicating that the combined use of XHX and CLZ can reduce the hepatotoxicity of CLZ. Herb-herb interactions could affect herb pharmacokinetics and in vivo efficacy. The herb-herb interactions between CLZ and XHX are still unknown.
This study used liquid chromatography tandem mass spectrometry (LC-MS) and gas chromatography tandem mass spectrometry (GC-MS) to establish methods for detecting toosendanin and trans-anethole, the main active substances of CLZ and XHX, respectively. Additionally, we investigated their herb-herb interactions via pharmacokinetic and pharmacodynamic studies.
The results indicate that the established analytical methods are suitable for detecting toosendanin and trans-anethole, and the methodology meets the requirements of biological sample testing methods. Compared with the CLZ group, the pharmacokinetic parameters C , AUC , AUC , MRT and MRT of toosendanin in the CLZ-XHX group notably decreased and the values of V remarkably increased. Compared with the XHX group, the pharmacokinetic parameters C , AUC , AUC T and t of trans-anethole notably increased in the CLZ-XHX group, and the values of CL and V obviously decreased.
The pharmacokinetic results indicate that XHX can significantly decrease the absorption and bioavailability and accelerate the elimination process of toosendanin in CLZ. XHX could decrease the risk of in vivo accumulation of the toxic constituent of CLZ, toosendanin, thus decreasing its toxicity. It has also been shown that CLZ can significantly increase absorption and bioavailability and attenuate the elimination process of trans-anethole in XHX, thus enhancing its efficacy. Hepatotoxicity studies indicate that CLZ has significant hepatotoxicity, and its combined use with XHX can decrease its liver-damaging properties.
中药配伍理论的目标是“减毒增效”，尤其用于解决许多中药的肝毒性问题。川楝子-小茴香是一对典型的能降低毒性并提高药效的中药药对。川楝子（性寒）具有显著的肝毒性。然而，在中医中，它与小茴香（性热）配伍使用已有数千年历史，在此配伍形式下它未表现出肝毒性，这表明小茴香与川楝子配伍使用可降低川楝子的肝毒性。药-药相互作用可能会影响药物的药代动力学和体内疗效。川楝子与小茴香之间的药-药相互作用尚不清楚。
本研究采用液相色谱串联质谱法（LC-MS）和气相色谱串联质谱法（GC-MS）分别建立检测川楝子和小茴香主要活性成分川楝素和反式茴香脑的方法。此外，我们通过药代动力学和药效学研究考察它们之间的药-药相互作用。
结果表明所建立的分析方法适用于检测川楝素和反式茴香脑，该方法学符合生物样品检测方法的要求。与川楝子组相比，川楝子-小茴香组中川楝素的药代动力学参数Cmax、AUC0-t、AUC0-∞、MRT0-t和MRT0-∞显著降低，Vz值显著升高。与小茴香组相比，川楝子-小茴香组中反式茴香脑的药代动力学参数Cmax、AUC0-t、AUC0-∞和t1/2显著升高，CL和Vz值明显降低。
药代动力学结果表明，小茴香可显著降低川楝子中川楝素的吸收和生物利用度，并加速其消除过程。小茴香可降低川楝子有毒成分川楝素在体内蓄积的风险，从而降低其毒性。研究还表明，川楝子可显著增加小茴香中反式茴香脑的吸收和生物利用度，并减弱其消除过程，从而增强其疗效。肝毒性研究表明，川楝子具有显著的肝毒性，其与小茴香配伍使用可降低其肝损伤特性。
