Abstract
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.
Highlights
The combination of Ephedra sinica Stapf (Mahuang) and Prunus armeniaca L. (Xingren) is a classical herb combination used to treat cold-induced asthma in traditional Chinese medicine (TCM) (Ma et al, 2021)
The XICs of blank rat plasma, blank plasma spiked with internal standards (IS) and analytes at LLOQ, and plasma samples after administration of traditional decoction and dispensing granules are shown in Supplementary Figure S3
Acceptable intraday and intraday precision and accuracy were demonstrated (88.3–113.0%; CV ≤ 13.3%) for matrix quality control (QC) samples (Supplementary Table S3). Both amygdalin and prunasin were quite stable under current storage and processing conditions, with variability ranging from −5.7 to 14.7% (CV ≤ 14.3%) (Supplementary Table S4)
Summary
The combination of Ephedra sinica Stapf (Mahuang) and Prunus armeniaca L. (Xingren) is a classical herb combination used to treat cold-induced asthma in traditional Chinese medicine (TCM) (Ma et al, 2021). Ephedrines in Mahuang and amygdalin of Xingren have been considered as the main active constituents possessing anti-asthmatic (Wang et al, 2021), anti-inflammatory (Karimi et al, 2021), and antitussive properties (Wang et al, 2019). The main active ingredient of Xingren is amygdalin (3% in Xingren) (Zhang et al, 2020). Amygdalin is metabolized by β-glucosidase, found in plants or the animal gut, into glucose and prunasin. Prunasin, a cyanogenic diglycoside, is metabolized into glucose and mandelonitrile, which are further hydrolyzed to benzaldehyde and hydrogen cyanide. Hydrogen cyanide is responsible for the antitussive properties of Xingren. The cyanogenesis metabolism pathway results in the release of hydrogen cyanide after oral administration of amygdalin and is a well-known mechanism for metabolic poisoning (Cressey and Reeve, 2019)
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