{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T07:29:36Z","timestamp":1774682976329,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:00:00Z","timestamp":1506384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Major Project of China","award":["2012ZX09301002\u2013001\u2013007"],"award-info":[{"award-number":["2012ZX09301002\u2013001\u2013007"]}]},{"DOI":"10.13039\/501100011636","name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines","doi-asserted-by":"publisher","award":["GTZA201303"],"award-info":[{"award-number":["GTZA201303"]}],"id":[{"id":"10.13039\/501100011636","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Project funded by China Postdoctoral Science Foundation","award":["2015M582145"],"award-info":[{"award-number":["2015M582145"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this study, we systematically investigated the plasma pharmacokinetics, tissue distribution, and elimination of three active alkaloids after oral administration of the effective fraction of alkaloids from Ramulus Mori (SZ\u2013A)\u2014an innovative hypoglycemic agent\u2014in rats. Moreover, the influences of other components in SZ\u2013A on dynamic process of alkaloids were explored for the first time. The results showed that 1-deoxynojirimycin (DNJ), fagomine (FGM) and 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) exhibited nonlinear pharmacokinetics following oral administration of SZ\u2013A (40\u20131000 mg\/kg). The prolonged t1\/2 and greater area under concentration-time curve (AUC) versus time (AUC0\u2013t) of DNJ for SZ\u2013A than for purified DNJ has been observed after both oral and intravenous administration. It was found that other components in SZ\u2013A could enhance the absorption of DNJ through the intestinal barrier. The major distribution tissues of DNJ, FGM, and DAB were the gastrointestinal tract, liver, and kidney. Three alkaloids were mainly excreted into urine and feces, but less into bile. Interestingly, the excess excretion of FGM was revealed to be partly due to the biotransformation of other components in SZ\u2013A via gut microbiota. These information provide a rational basis for the use of SZ\u2013A in clinical practice.<\/jats:p>","DOI":"10.3390\/molecules22101616","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T16:14:45Z","timestamp":1506442485000},"page":"1616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pharmacokinetics, Tissue Distribution, and Elimination of Three Active Alkaloids in Rats after Oral Administration of the Effective Fraction of Alkaloids from Ramulus Mori, an Innovative Hypoglycemic Agent"],"prefix":"10.3390","volume":"22","author":[{"given":"Shuang","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK\/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Department of Pharmaceutical Analysis, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Mi","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK\/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK\/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baolian","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK\/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuejun","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuling","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK\/PD Study, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.2337\/dc09-9032","article-title":"Hyperglycemic crises in adult patients with diabetes","volume":"32","author":"Kitabchi","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_2","unstructured":"Federation, I.D. (2015, November 29). Idf Diabetes Atlas 7th Edition. Available online: http:\/\/www.diabetesatlas.org\/."},{"key":"ref_3","first-page":"343594","article-title":"Treating type 2 diabetes mellitus with traditional Chinese and Indian medicinal herbs","volume":"2013","author":"Wang","year":"2013","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"521","DOI":"10.2165\/00003495-200059030-00012","article-title":"Miglitol: A review of its therapeutic potential in type 2 diabetes mellitus","volume":"59","author":"Scott","year":"2000","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Bolen, S., Wilson, L., Vassy, J., Feldman, L., Yeh, J., Marinopoulos, S., Wilson, R., Cheng, D., Wiley, C., and Selvin, E. (2007). Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes, Agency for Healthcare Research and Quality.","DOI":"10.7326\/0003-4819-147-6-200709180-00178"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1078\/0944-7113-00065","article-title":"\u03b1-glucosidaseinhibition from a chinese medical herb (Ramulus Mori) in normal and diabetic rats and mice","volume":"9","author":"Ye","year":"2002","journal-title":"Phytomedicine"},{"key":"ref_7","first-page":"108","article-title":"Experimental treatment of complications in alloxan diabetic rats with \u03b1-glucosidase inhibitor from the Chinese medicinal herb Ramulus Mori","volume":"37","author":"Ye","year":"2002","journal-title":"Yao Xue Xue Bao"},{"key":"ref_8","unstructured":"Liu, Y., Shen, Z., Chen, Z., Wang, R., Xia, X., Chen, Y., Liu, Q., Sun, S., and Xie, M. (2015). Use of the Effective Fraction of Alkaloids from Mulberry Twig in Preparing Hypoglycemic Agents. (12\/674532), U.S. Patent."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1155\/2016\/7121356","article-title":"Randomized, double-blinded, double-dummy, active-controlled, and multiple-dose clinical study comparing the efficacy and safety of mulberry twig (Ramulus Mori, Sangzhi) alkaloid tablet and acarbose in individuals with type 2 diabetes mellitus","volume":"2016","author":"Li","year":"2016","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8928","DOI":"10.1021\/jf071559m","article-title":"Occurrence of orally administered mulberry 1-deoxynojirimycin in rat plasma","volume":"55","author":"Nakagawa","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jpba.2015.02.019","article-title":"Simultaneous quantification of three active alkaloids from a traditional Chinese medicine Ramulus Mori (Sangzhi) in rat plasma using liquid chromatography-tandem mass spectrometry","volume":"109","author":"Yang","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1046\/j.1463-1326.2003.00293.x","article-title":"Pharmacokinetics and anti-hyperglycaemic efficacy of a novel inhibitor of glycogen phosphorylase, 1,4-dideoxy-1,4-imino-d-arabinitol, in glucagon-challenged rats and dogs and in diabetic ob\/ob mice","volume":"5","author":"Mackay","year":"2003","journal-title":"Diabetes Obes. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6666","DOI":"10.1021\/jf100322y","article-title":"Comparison of absorption of 1-deoxynojirimycin from mulberry water extract in rats","volume":"58","author":"Kim","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.jep.2013.11.038","article-title":"Pharmacokinetic mechanism of enhancement by Radix Pueraria flavonoids on the hyperglycemic effects of Cortex Mori extract in rats","volume":"151","author":"Xiao","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/bmc.781","article-title":"Permeability of atenolol and propranolol in the presence of dimethyl sulfoxide in rat single-pass intestinal perfusion assay with liquid chromatography\/UV detection","volume":"21","author":"Venkatesh","year":"2007","journal-title":"Biomed. Chromatogr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0006-2952(88)90179-7","article-title":"1-deoxynojirimycin and related compounds inhibit glycogenolysis in the liver without affecting the concentration of phosphorylase a","volume":"37","author":"Bollen","year":"1988","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1111\/j.1432-1033.1989.tb14792.x","article-title":"The antiglycogenolytic action of 1-deoxynojirimycin results from a specific inhibition of the \u03b1-1,6-glucosidase activity of the debranching enzyme","volume":"181","author":"Bollen","year":"1989","journal-title":"Eur. J. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.bcp.2003.09.036","article-title":"Inhibition of glycogen breakdown by imino sugars in vitro and in vivo","volume":"67","author":"Andersson","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1021\/np960646y","article-title":"Fagomine isomers and glycosides from Xanthocercis zambesiaca","volume":"60","author":"Kato","year":"1997","journal-title":"J. Nat. Prod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10719-009-9276-3","article-title":"Cytotoxicity and enzymatic activity inhibition in cell lines treated with novel iminosugar derivatives","volume":"27","author":"Castillo","year":"2010","journal-title":"Glycoconj. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1017\/S0007114511005009","article-title":"D-fagomine lowers postprandial blood glucose and modulates bacterial adhesion","volume":"107","author":"Adelantado","year":"2012","journal-title":"Br. J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1006\/abbi.2000.1930","article-title":"Kinetic and functional characterization of 1,4-dideoxy-1,4-imino-d-arabinitol: A potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob\/ob mice","volume":"380","author":"Fosgerau","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1002\/jps.20309","article-title":"Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability","volume":"94","author":"Varma","year":"2005","journal-title":"J. Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/nature11552","article-title":"Functional interactions between the gut microbiota and host metabolism","volume":"489","author":"Tremaroli","year":"2012","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/0140-6736(91)92302-I","article-title":"First-pass metabolism of cyclosporin by the gut","volume":"338","author":"Kolars","year":"1991","journal-title":"Lancet"},{"key":"ref_26","first-page":"14","article-title":"First-pass metabolism of midazolam by the human intestine","volume":"60","author":"Paine","year":"1996","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2008.07.009","article-title":"The gastrointestinal microbiota as a site for the biotransformation of drugs","volume":"363","author":"Sousa","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"486","DOI":"10.2133\/dmpk.DMPK-11-RG-142","article-title":"Role of P-glycoprotein in intestinal absorption of fb2, a promising abl\/src dual tyrosine kinase inhibitor","volume":"27","author":"Huang","year":"2012","journal-title":"Drug Metab. Pharmacok."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/10\/1616\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:46:01Z","timestamp":1760208361000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/10\/1616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,26]]},"references-count":28,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["molecules22101616"],"URL":"https:\/\/doi.org\/10.3390\/molecules22101616","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,26]]}}}