DataSheet1_Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin.docx

Mahuang–Xingren (MX, Ephedra sinica Stapf-Prunus armeniaca L.) is a classic herb pair used in traditional Chinese medicine. This combined preparation reduces the toxicity of Xingren through the stereoselective metabolism of its main active ingredient amygdalin. However, whether stereoselectivity is important in the pharmacokinetic properties of amygdalin either in the traditional decoction or in the dispensing granules is unclear. Amygdalin is hydrolyzed to its metabolite, prunasin, which produces hydrogen cyanide by degradation of the cyano group. A comprehensive study of the metabolic pathway of amygdalin is essential to better understand the detoxification process. In this article, the potential detoxification pathway of MX is further discussed with regard to herb interactions. In this study, the pharmacokinetic parameters and metabolism of amygdalin and prunasin were investigated by comparing the traditional decoction and the dispensing granule preparations. In addition, several potential metabolites were characterized in an incubation system with rat liver microsomes or gut microbial enzymes. The combination of Xingren with Mahuang reduces exposure to D-amygdalin in vivo and contributes to its detoxification, a process that can be further facilitated in the traditional decoction. From the in vitro co-incubation model, 15 metabolites were identified and classified into cyanogenesis and non-cyanogenesis metabolic pathways, and of these, 10 metabolites were described for the first time. The level of detoxified metabolites in the MX traditional decoction was higher than that in the dispensing granules. The metabolism of amygdalin by the gut microbial enzymes occurred more rapidly than that by the rat liver microsomes. These results indicated that combined boiling both herbs during the preparation of the traditional decoction may induce several chemical changes that will influence drug metabolism in vivo. The gut microbiota may play a critical role in amygdalin metabolism. In conclusion, detoxification of MX may result 1) during the preparation of the decoction, in the boiling phase, and 2) from the metabolic pathways activated in vivo. Stereoselective pharmacokinetics and deamination metabolism have been proposed as the detoxification pathway underlying the compatibility of MX. Metabolic detoxification of amygdalin was quite different between the two combinations, which indicates that the MX decoctions should not be completely replaced by their dispensing granules.

麻黄-杏仁（MX，草麻黄（Ephedra sinica Stapf）-杏（Prunus armeniaca L.））是中药经典药对。该配伍复方可通过对其主要活性成分苦杏仁苷（amygdalin）的立体选择性代谢，降低杏仁的毒性。然而，目前尚不明确，在传统汤剂与配方颗粒（dispensing granules）两种制剂中，立体选择性对苦杏仁苷的药代动力学特性是否具有关键影响。苦杏仁苷可水解为代谢产物野樱苷（prunasin），野樱苷可通过氰基降解产生氰化氢（hydrogen cyanide）。全面解析苦杏仁苷的代谢通路，对于深入阐释其解毒机制至关重要。本文围绕药对相互作用，进一步探讨了MX的潜在解毒通路。本研究通过对比传统汤剂与配方颗粒两种制剂，考察了苦杏仁苷与野樱苷的药代动力学参数及代谢特征。此外，本研究在大鼠肝微粒体（rat liver microsomes）与肠道菌群酶（gut microbial enzymes）的孵育体系中，对多种潜在代谢产物进行了结构表征。麻黄与杏仁配伍可降低体内D-苦杏仁苷的暴露量，进而发挥解毒作用，且该过程在传统汤剂中可得到进一步强化。通过体外共孵育模型，本研究共鉴定出15种代谢产物，可分为产氰代谢途径（cyanogenesis）与非产氰代谢途径（non-cyanogenesis）两类，其中10种代谢产物为首次报道。MX传统汤剂中解毒性代谢产物的水平高于配方颗粒。肠道菌群酶对苦杏仁苷的代谢速率快于大鼠肝微粒体。上述结果表明，在传统汤剂的制备过程中，将两药共煎可引发多种化学变化，进而影响体内药物代谢过程。肠道菌群可能在苦杏仁苷的代谢过程中发挥关键作用。综上，MX的解毒作用可能源于两个途径：1）汤剂制备过程中的煎煮阶段，2）体内激活的代谢通路。立体选择性药代动力学与脱氨基代谢（deamination）被认为是MX配伍发挥解毒作用的潜在通路。两种制剂中苦杏仁苷的代谢解毒过程存在显著差异，这表明MX传统汤剂不应被配方颗粒完全替代。