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Deoxyschizandrin and schisantherin A are major bioactive lignans isolated from Fructusschisandrae which has been widely used as a tonic in traditional Chinese medicine for manyyears. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be animportant reason for clinical herb–drug interaction. The aim of the present study is toinvestigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGTisoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 μM ofdeoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligibleinhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin Awere demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC50 valueof 10.8±0.4 μM and 12.5±0.5 μM, respectively. Dixon and Lineweaver–Burk plots showedthat inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, andinhibition kinetic parameter (Ki) was calculated to be 0.48 μM. Inhibition of UGT1A3 byschisantherin A gave the best fit for types of noncompetitive inhibition, and the results showedKi to be 11.3 μM. All these experimental data suggested that herb–drug interaction might occurwhen deoxyschizandrin or schisantherin A containing herbs were co-administered with drugswhich mainly undergo UGT1A3-mediated metabolism. However, given that many in vivofactors could influence the in vitro–in vivo extrapolation (IVIVE), these in vitro inhibitoryparameters should be considered with caution.

The detailed mechanisms on licorice-drug interaction remain to be unclear. The aim of the present study is to investigate the inhibition of important UGT isoforms by two important ingredients of licorice, liquiritin, and liquiritigenin. The results showed that liquiritigenin exhibited stronger inhibition towards all the tested UGT isoforms than liquiritin. Data fitting using Dixon and Lineweaver-Burk plots demonstrated the competitive inhibition of liquiritigenin towards UGT1A1 and UGT1A9-mediated 4-MU glucuronidation reaction. The inhibition kinetic parameters (Ki ) were calculated to be 9.1 and 3.2 μM for UGT1A1 and UGT1A9, respectively. Substrate-dependent inhibition behaviour was also observed for UGT1A1 in the present study. All these results will be helpful for understanding the deep mechanism of licorice-drug interaction. However, when translating these in vitro parameters into in vivo situations, more complex factors should be considered, such as substrate-dependent inhibition of UGT isoforms, the contribution of UGT1A1 and UGT1A9 towards the metabolism of drugs, and many factors affecting the abundance of ingredients in the licorice.

Traditional Chinese medicine (TCM) formulas with fixed combinations rely on "sovereign, minister, assistant and guide" and fuzzy mathematical quantitative law, leading to greater challenges for the identification of active ingredients. Transformation and metabolic studies involving the Phase I drug-metabolizing enzyme cytochrome P450 (CYP) might potentially solve some of these challenges. The pharmacological effects can not be attributed to one active ingredient in TCMs, but integrated effects resulting from the combined actions of multiple ingredients. However, it is only after long-term administration that most ingredients exert their actions, which can result in prolonged exposure to herbs in vivo. Therefore, interactions between herbal compounds and CYPs appear to be inevitable. Yet unlike Western drugs, experimental determination of the absorption and disposition properties is not commonly carried out for TCMs. Moreover, the use of TCM as injections is an innovation aimed to improve efficiency in extensive clinical use in Mainland China. Therefore, in recent years, cases of adverse drug reactions (ADR) mainly concerning allergic reactions involving TCMs such as ShenMai injection and QingKaiLing injection have been reported, which have attracted attention with regard to the legal responsibilities for TCM approval. The lack of information on the ADME characteristics, especially the metabolic stability and interaction potential between CYPs and herbs, increases ADR occurrence due to TCMs. In this article, we review the most common herbs used in TCM prescriptions and fixed combinations of their usable frequency, and summarize the current understanding of the ability of phytochemical ingredients to act as substrates, inhibitors or inducers of human CYP enzymes, through which the key role of CYP enzymes on the herb disposition and toxicity is highlighted. The potential interaction between herbal phytochemicals and CYP enzymes dominates the target exposure, which further helps to elucidate the herbal pharmacological basis, assess the individual toxic risk of herbal remedies and gain mechanistic insight into herb-drug interactions (HDIs).