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Studies on Efficacy Mechanism of Chinese Herbal Combination Based on Drug metabolizing Enzyme

Xiaogang Weng, Yue Gao, Yujie Li, Xiaoni Liu, Ying Chen, Qing Yang, Yu Dong, Zipeng Gong, Yajie Wang, Qi Li1, Feng Sui and Xiaoxin Zhu

Mixed Formula is the main form and method of Traditional Chinese Medicine (TCM) treatment. It can produce different therapeutic effects by changing the combination of TCM Formula. Wuji Wan is a formula of TCM and was composed of Rhizoma Coptidis (Huanglian in Chinese, HL), Fructus Evodiae Rutaecarpae (Wuzhuyu, WZY) and Radix Paeoniae Alba (Baishao, BS). Wuji Wan is mainly used for the treatment of intestinal diseases. This paper took Wuji Wan as example study on efficacy Mechanism of TCM Combination Based on drug metabolizing Enzyme. Inhibition of cytochrome P450 (CYP) is regarded as the most clinically important pharmacokinetic causes among the various possible factors for drug-drug or herb-herb/herb-drug interactions. In this study, the in vitro inhibitory effects of Wuji Wan with different combination within HL, WZY and BS on six major rat CYPs (CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A1/3A2) activities were examined by using HPLC and LC-MS. Wuji Wan with different combination were designed as 9 Formulae according to orthogonal table L₉ (3⁴); meanwhile the inhibitory effects of the single herb HL, WZY and BS also were done and compared with 9 Wuji Wan Formulae with different combination. Results demonstrated that BS showed negligible inhibitory effects on the six major CYP isoenzymes in rat liver microsomes, but HL showed strong inhibitory effects on 6 CYPs with almost all of the IC₅₀ values below 200 μg (crude drug)•mL^-1, and WZY showed a little bit inhibitory effects on 6 CYPs with the IC₅₀ values between 870-2000 μg (crude drug)•mL^-1; moreover, 9 Wuji Wan Formulae showed different inhibitory characteristic following with the dose levels of HL, WZY and BS in L9(34) design. In conclusion, this study demonstrates that Wuji Wan is likely to cause significant herb-drug interactions in humans when co-administered with substrates of the six CYPs (CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A)and also the different inhibitory effects on cytochrome P450 of Wuji Wan within different combination could be one of the reasons for explaining the different combination of TCM Formula producing different therapeutic effects, because the chemical composition of TCM in vivo (prototype or metabolites) is the Material basis of TCM effects.