Determination of toosendanin and trans‐anethole in Fructus Meliae Toosendan and Fructus Foeniculi by HPLC–MS/MS and GC–MS/MS in rat plasma and their potential herb–herb interactions

Abstract

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 Cmax , AUC(0-t) , AUC(0-∞) , MRT(0-t) and MRT(0-∞) of toosendanin in the CLZ-XHX group notably decreased and the values of Vz/F remarkably increased. Compared with the XHX group, the pharmacokinetic parameters Cmax , AUC0-t , AUC0-∞, Tmax and t1/2z of trans-anethole notably increased in the CLZ-XHX group, and the values of CLz/F and Vz/F 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.