{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:10:44Z","timestamp":1782817844911,"version":"3.54.5"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81703800"],"award-info":[{"award-number":["81703800"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Mahuang\u2013Xingren (MX, <jats:italic>Ephedra sinica<\/jats:italic> Stapf-<jats:italic>Prunus armeniaca<\/jats:italic> 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 <jats:italic>main active ingredient<\/jats:italic> 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 <jats:italic>D<\/jats:italic>-amygdalin <jats:italic>in vivo<\/jats:italic> and contributes to its detoxification, a process that can be further facilitated in the traditional decoction. From the <jats:italic>in vitro<\/jats:italic> 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 <jats:italic>in vivo<\/jats:italic>. 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 <jats:italic>in vivo<\/jats:italic>. 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.<\/jats:p>","DOI":"10.3389\/fphar.2021.744624","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T07:09:19Z","timestamp":1638342559000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin"],"prefix":"10.3389","volume":"12","author":[{"given":"Yan","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyu","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlin","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s13065-017-0365-2","article-title":"LC-MS\/MS Method for the Quantification of Masitinib in RLMs Matrix and Rat Urine: Application to Metabolic Stability and Excretion Rate","volume":"11","author":"Amer","year":"2017","journal-title":"Chem. Cent. J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jpba.2018.07.032","article-title":"LC-MS\/MS Reveals the Formation of Iminium and Quinone Methide Reactive Intermediates in Entrectinib Metabolism: In Vivo and In Vitro Metabolic Investigation","volume":"160","author":"Attwa","year":"","journal-title":"J. Pharm. Biomed. Anal."},{"key":"B3","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1177\/1469066718768327","article-title":"A Reliable and Stable Method for the Determination of Foretinib in Human Plasma by LC-MS\/MS: Application to Metabolic Stability Investigation and Excretion Rate","volume":"24","author":"Attwa","year":"","journal-title":"Eur. J. Mass. Spectrom. (Chichester)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1021\/acs.analchem.6b04834","article-title":"Ultrafast Chiral Chromatography as the Second Dimension in Two-Dimensional Liquid Chromatography Experiments","volume":"89","author":"Barhate","year":"2017","journal-title":"Anal. Chem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.phymed.2016.02.004","article-title":"Amygdalin, Quackery or Cure?","volume":"23","author":"Blaheta","year":"2016","journal-title":"Phytomedicine"},{"key":"B6","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1021\/acs.analchem.7b03996","article-title":"Determination of Urinary Metabolites of the Emerging UV Filter Octocrylene by Online-SPE-LC-MS\/MS","volume":"90","author":"Bury","year":"2018","journal-title":"Anal. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.toxlet.2019.05.017","article-title":"Evaluation of the Inhibition Risk of Shikonin on Human and Rat UDP-Glucuronosyltransferases (UGT) through the Cocktail Approach","volume":"312","author":"Cheng","year":"2019","journal-title":"Toxicol. Lett."},{"key":"B8","volume-title":"Pharmacopoeia of the People's Republic of China","author":"Commission","year":"2015"},{"key":"B9","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.fct.2019.01.002","article-title":"Metabolism of Cyanogenic Glycosides: A Review","volume":"125","author":"Cressey","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jep.2019.03.025","article-title":"Quality Marker Identification Based on Standard Decoction of Differently Processed Materials of Ephedrae Herba","volume":"237","author":"Dai","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1080\/17474124.2021.1898944","article-title":"Patients with Inflammatory Bowel Disease (IBD) Prefer Oral Tablets over Other Modes of Medicine Administration","volume":"15","author":"Denesh","year":"2021","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.yrtph.2018.01.027","article-title":"Assessing the Safety of an Ephedrae Herba Aqueous Extract in Rats: A Repeat Dose Toxicity Study","volume":"94","author":"Han","year":"2018","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.2165\/00003495-200565090-00005","article-title":"Herb-drug Interactions: a Literature Review","volume":"65","author":"Hu","year":"2005","journal-title":"Drugs"},{"key":"B14","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1007\/s40262-019-00740-w","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Transarterial Chemoembolization and Targeted Therapies in Hepatocellular Carcinoma","volume":"58","author":"Hulin","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2997","DOI":"10.1002\/ptr.7006","article-title":"Almond as a Nutraceutical and Therapeutic Agent in Persian Medicine and Modern Phytotherapy: A Narrative Review","volume":"35","author":"Karimi","year":"2021","journal-title":"Phytother. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1093\/jn\/nxab032","article-title":"Hepatoprotective Effects of Indole, a Gut Microbial Metabolite, in Leptin-Deficient Obese Mice","volume":"151","author":"Knudsen","year":"2021","journal-title":"J. Nutr."},{"key":"B17","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1111\/jpn.13055","article-title":"Potential Toxicity of Cyanogenic Glycoside Amygdalin and Bitter Apricot Seed in Rabbits-Health Status Evaluation","volume":"103","author":"Kovacikova","year":"2019","journal-title":"J. Anim. Physiol. Anim. Nutr. (Berl)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.talanta.2017.06.009","article-title":"Preparation and Evaluation of a Novel N-Benzyl-Phenethylamino-\u03b2-Cyclodextrin-Bonded Chiral Stationary Phase for HPLC","volume":"174","author":"Li","year":"2017","journal-title":"Talanta"},{"key":"B19","doi-asserted-by":"publisher","first-page":"113745","DOI":"10.1016\/j.jep.2020.113745","article-title":"Herb Pair of Ephedrae Herba-Armeniacae Semen Amarum Alleviates Airway Injury in Asthmatic Rats","volume":"269","author":"Ma","year":"2021","journal-title":"J. Ethnopharmacology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1016\/j.ultrasmedbio.2015.12.022","article-title":"Changes in Dorsal Neck Muscle Function in Individuals with Chronic Whiplash-Associated Disorders: A Real-Time Ultrasound Case-Control Study","volume":"42","author":"Peterson","year":"2016","journal-title":"Ultrasound Med. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1042\/BJ20150390","article-title":"A Recycling Pathway for Cyanogenic Glycosides Evidenced by the Comparative Metabolic Profiling in Three Cyanogenic Plant Species","volume":"469","author":"Pi\u010dmanov\u00e1","year":"2015","journal-title":"Biochem. J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"153266","DOI":"10.1016\/j.phymed.2020.153266","article-title":"Network Pharmacology Combined with Metabolomics Approach to Investigate the Protective Role and Detoxification Mechanism of Yunnan Baiyao Formulation","volume":"77","author":"Ren","year":"2020","journal-title":"Phytomedicine"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3546","DOI":"10.1021\/acs.jmedchem.0c01930","article-title":"Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization","volume":"64","author":"Sodhi","year":"2021","journal-title":"J. Med. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.jep.2015.12.019","article-title":"Stereoselective Metabolism of Amygdalin-Based Study of Detoxification of Semen Armeniacae Amarum in the Herba Ephedrae-Semen Armeniacae Amarum Herb Pair","volume":"179","author":"Song","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0230197","DOI":"10.1371\/journal.pone.0230197","article-title":"Effects of Intestinal flora on the Pharmacokinetics and Pharmacodynamics of Aspirin in High-Altitude Hypoxia","volume":"15","author":"Sun","year":"2020","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e4","DOI":"10.1017\/erm.2018.3","article-title":"What Has Traditional Chinese Medicine Delivered for Modern Medicine?","volume":"20","author":"Wang","year":"2018","journal-title":"Expert Rev. Mol. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"590824","DOI":"10.3389\/fphar.2020.590824","article-title":"Network Patterns of Herbal Combinations in Traditional Chinese Clinical Prescriptions","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"107151","DOI":"10.1016\/j.intimp.2020.107151","article-title":"Amygdalin Inhibits TGF\u03b21-Induced Activation of Hepatic Stellate Cells (HSCs) In Vitro and CCl4-Induced Hepatic Fibrosis in Rats In Vivo","volume":"90","author":"Wang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.jep.2012.07.033","article-title":"Compatibility Art of Traditional Chinese Medicine: from the Perspective of Herb Pairs","volume":"143","author":"Wang","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1002\/ptr.6274","article-title":"Protective Effect of Amygdalin on Epithelial-Mesenchymal Transformation in Experimental Chronic Obstructive Pulmonary Disease Mice","volume":"33","author":"Wang","year":"2019","journal-title":"Phytother. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"111998","DOI":"10.1016\/j.fct.2021.111998","article-title":"Inhibition of Drug-Metabolizing Enzymes by Qingfei Paidu Decoction: Implication of Herb-Drug Interactions in COVID-19 Pharmacotherapy","volume":"149","author":"Zhang","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"140146","DOI":"10.1016\/j.scitotenv.2020.140146","article-title":"Aqueous Chlorination of Ephedrine: Kinetic, Reaction Mechanism and Toxicity Assessment","volume":"740","author":"Zhang","year":"2020","journal-title":"Sci. Total Environ."},{"key":"B33","doi-asserted-by":"publisher","first-page":"624296","DOI":"10.3389\/fphar.2021.624296","article-title":"The Analyses of Chemical Components from Oldenlandia Hedyotidea (DC.) Hand.-Mazz and Anticancer Effects In Vitro","volume":"12","author":"Zhao","year":"","journal-title":"Front. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"153315","DOI":"10.1016\/j.phymed.2020.153315","article-title":"Systems Pharmacological Study Illustrates the Immune Regulation, Anti-infection, Anti-inflammation, and Multi-Organ protection Mechanism of Qing-Fei-Pai-Du Decoction in the Treatment of COVID-19","volume":"85","author":"Zhao","year":"","journal-title":"Phytomedicine"}],"updated-by":[{"DOI":"10.3389\/fphar.2021.831921","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.744624\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T08:42:17Z","timestamp":1640940137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.744624\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":34,"alternative-id":["10.3389\/fphar.2021.744624"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.744624","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fphar.2021.831921","asserted-by":"object"}]},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]},"article-number":"744624"}}