{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:35:22Z","timestamp":1760060122331,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Natural Science Basic Research Program of Shaanxi Provincial Department of Science and Technology","award":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"],"award-info":[{"award-number":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"]}]},{"name":"Open Experimental Research Fund for College Students of Xi\u2019an Medical University","award":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"],"award-info":[{"award-number":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"]}]},{"name":"The Key Research and Development Program of Shaanxi","award":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"],"award-info":[{"award-number":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"]}]},{"name":"Research start-up fund of Xi\u2019an Medical University","award":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"],"award-info":[{"award-number":["2024JC-YBQN-0956","2024DXS28","2024DXS45","2021ZDLSF03-05","2021DOC17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The novel compound 221s (2,9), derived from danshensu and ACEI-active proline, exhibits antihypertensive effects (50\/35 mmHg SBP\/DBP reduction in SHRs) with potential cough mitigation. However, its excretion kinetics remain unstudied. This study investigates 221s (2,9) elimination in rats to bridge this knowledge gap. Methods: Excretion of unchanged 221s (2,9) was quantified in urine, feces, and bile of Sprague-Dawley rats after oral administration (30 mg\/kg). Concentrations of unchanged 221s (2,9) in all matrices were quantified using developed UPLC-MS\/MS that underwent methodological validation. Excretion amount, excretion velocity, and accumulative excretion rate of 221s (2,9) were calculated. Results: Urinary excretion exhibited rapid elimination kinetics, reaching peak cumulative excretion rates (138.81 \u00b1 15.56 ng\/h) at 8 h post-dosing and plateauing by 48 h (cumulative excretion: 1479.81 \u00b1 155.7 ng). Fecal excretion displayed an accelerated elimination phase between 4 and 8 h (excretion rate: 7994.29 \u00b1 953.75 ng\/h), followed by a sustained slow-release phase, culminating in a cumulative output of 36,726.31 \u00b1 5507 ng at 48 h. Biliary excretion was minimal and ceased entirely by 24 h. Notably, total recovery of unchanged drug across all matrices remained below 1% (urine: 0.020 \u00b1 0.021%; feces: 0.73 \u00b1 0.069%; bile: 0.00044 \u00b1 0.00002%) at 72 h. Conclusions: This study provides the first definitive excretion data for 221s (2,9). Quantitative analysis via a validated UPLC-MS\/MS method revealed that fecal excretion is the principal elimination pathway for unchanged 221s (2,9) in rats, with direct excretion of the parent compound accounting for &lt;1% of the administered dose over 72 h. Future studies will employ extended pharmacokinetic monitoring and concurrent UPLC-MS\/MS analysis of the parent drug and phase II conjugates to resolve the observed mass imbalance and elucidate contributions to total elimination.<\/jats:p>","DOI":"10.3390\/ph18081138","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:29:02Z","timestamp":1753885742000},"page":"1138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Study on the Excretion of a New Antihypertensive Drug 221s (2,9) in Rats"],"prefix":"10.3390","volume":"18","author":[{"given":"Yunmei","family":"Chen","sequence":"first","affiliation":[{"name":"Xi\u2019an Key Laboratory for Research and Development of Innovative Multi-Target Antihypertensive Drugs, Xi\u2019an Innovative Antihypertensive Drugs International Science and Technology Cooperation Base, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"Institute of Drug Research, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"College of Pharmacy, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Xi\u2019an Key Laboratory for Research and Development of Innovative Multi-Target Antihypertensive Drugs, Xi\u2019an Innovative Antihypertensive Drugs International Science and Technology Cooperation Base, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"Institute of Drug Research, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"College of Pharmacy, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaojing","family":"Liu","sequence":"additional","affiliation":[{"name":"Xi\u2019an Key Laboratory for Research and Development of Innovative Multi-Target Antihypertensive Drugs, Xi\u2019an Innovative Antihypertensive Drugs International Science and Technology Cooperation Base, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"Institute of Drug Research, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"College of Pharmacy, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lili","family":"Yu","sequence":"additional","affiliation":[{"name":"Xi\u2019an Key Laboratory for Research and Development of Innovative Multi-Target Antihypertensive Drugs, Xi\u2019an Innovative Antihypertensive Drugs International Science and Technology Cooperation Base, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"Institute of Drug Research, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"College of Pharmacy, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Xi\u2019an Key Laboratory for Research and Development of Innovative Multi-Target Antihypertensive Drugs, Xi\u2019an Innovative Antihypertensive Drugs International Science and Technology Cooperation Base, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"Institute of Drug Research, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"College of Pharmacy, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Qin","sequence":"additional","affiliation":[{"name":"Xi\u2019an Key Laboratory for Research and Development of Innovative Multi-Target Antihypertensive Drugs, Xi\u2019an Innovative Antihypertensive Drugs International Science and Technology Cooperation Base, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"Institute of Drug Research, Xi\u2019an Medical University, Xi\u2019an 710021, China"},{"name":"College of Pharmacy, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ejim.2023.12.026","article-title":"Resistant hypertension: Diagnosis, evaluation, and treatment practical approach","volume":"123","author":"Parodi","year":"2024","journal-title":"Eur. J. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.numecd.2021.09.007","article-title":"Arterial hypertension\u2014Clinical trials update 2021","volume":"32","author":"Gotzinger","year":"2022","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1093\/eurheartj\/ehac395","article-title":"Hypertension management in patients with cardiovascular comorbidities","volume":"44","author":"Lauder","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1001\/jama.2022.19590","article-title":"Treatment of Hypertension: A Review","volume":"328","author":"Carey","year":"2022","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rysz, J., Franczyk, B., Rysz-Gorzynska, M., and Gluba-Brzozka, A. (2020). Pharmacogenomics of Hypertension Treatment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134709"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3122\/jabfm.2022.220276R1","article-title":"Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Angioedema of the Small Bowel: A Diagnostic Dilemma","volume":"36","author":"Niyibizi","year":"2023","journal-title":"J. Am. Board. Fam. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yao, T., Wu, Z., Wang, Z., Chen, L., Liu, B., Lu, M., and Shen, N. (2023). Association between angiotensin-converting enzyme inhibitor-induced cough and the risk of lung cancer: A Mendelian randomization study. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1267924"},{"key":"ref_8","first-page":"S38","article-title":"A novel drug discovery strategy inspired by traditional medicine philosophies","volume":"347","author":"Zhao","year":"2015","journal-title":"Science"},{"key":"ref_9","first-page":"405","article-title":"Research strategy for Combination of Traditional Chinese Medicine Molecular Chemistry based on the traditional theory of \u2018Jun-Chen-Zuo-Shi\u2019","volume":"45","author":"Pu","year":"2015","journal-title":"J. Northwest Univ."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Qin, B., Chen, Y., Yang, K., Wang, R., Yu, L., Wang, N., and Liu, S. (2024). An Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS\/MS) Method for Qualifying DAPB in Rat Plasma and Application to Pharmacokinetic Studies. Molecules, 29.","DOI":"10.3390\/molecules29020541"},{"key":"ref_11","first-page":"754","article-title":"The study on acute toxicity test of anti-hypertensive new drug proline Danshensu borneol ester on mice","volume":"20","author":"Wang","year":"2023","journal-title":"Chin. J. Pharmacovigil."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Qin, B., Yu, L., Wang, R., Tang, Y., Chen, Y., Wang, N., Zhang, Y., Tan, X., Yang, K., and Zhang, B. (2023). Chemical Synthesis, Safety and Efficacy of Antihypertensive Candidate Drug 221s (2,9). Molecules, 28.","DOI":"10.3390\/molecules28134975"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1016\/j.apsb.2022.03.009","article-title":"Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development","volume":"12","author":"Lai","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1124\/dmd.123.001437","article-title":"Metabolism and Excretion of Therapeutic Peptides: Current Industry Practices, Perspectives, and Recommendations","volume":"51","author":"He","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tran, T.T.V., Tayara, H., and Chong, K.T. (2023). Artificial Intelligence in Drug Metabolism and Excretion Prediction: Recent Advances, Challenges, and Future Perspectives. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15041260"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yang, C., Xue, M., He, Y., Yin, H., Yang, C., Zhong, D., Zeng, H., Zheng, Y., and Diao, X. (2023). Absorption, Distribution, Metabolism, and Excretion of [(14)C]BS1801, a Selenium-Containing Drug Candidate, in Rats. Molecules, 28.","DOI":"10.3390\/molecules28248102"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.jep.2015.01.003","article-title":"Improved blood-brain barrier distribution: Effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling","volume":"162","author":"Zhang","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1016\/j.lfs.2004.06.010","article-title":"Protective effects of Danshensu from the aqueous extract of Salvia miltiorrhiza (Danshen) against homocysteine-induced endothelial dysfunction","volume":"75","author":"Chan","year":"2004","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Du, X., Tao, Q., Du, H., Zhao, Z., Dong, Y., He, S., Shao, R., Wang, Y., Han, W., and Wang, X. (2021). Tengdan Capsule Prevents Hypertensive Kidney Damage in SHR by Inhibiting Periostin-Mediated Renal Fibrosis. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.638298"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cao, Y., Lu, K., Xia, Y., Wang, Y., Wang, A., and Zhao, Y. (2022). Danshensu Attenuated Epithelial-Mesenchymal Transformation and Chemoresistance of Colon Cancer Cells Induced by Platelets. Front. Biosci., 27.","DOI":"10.31083\/j.fbl2705160"},{"key":"ref_21","first-page":"153656","article-title":"Danshensu derivative ADTM ameliorates CCl4-induced acute liver injury in mice through inhibiting oxidative stress and apoptosis","volume":"228","author":"Jia","year":"2021","journal-title":"Pathology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.vph.2006.10.011","article-title":"Relaxant effects of danshen aqueous extract and its constituent danshensu on rat coronary artery are mediated by inhibition of calcium channels","volume":"46","author":"Lam","year":"2007","journal-title":"Vasc. Pharmacol."},{"key":"ref_23","first-page":"S10","article-title":"Developmental Changes in Pharmacokinetics and Pharmacodynamics","volume":"58","author":"Reed","year":"2018","journal-title":"J. Clin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1124\/dmd.122.001006","article-title":"Human Absorption, Distribution, Metabolism, and Excretion Studies: Origins, Innovations, and Importance","volume":"51","author":"Cerny","year":"2023","journal-title":"Drug Metab. Dispos."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.apsb.2018.04.003","article-title":"Drug metabolism in drug discovery and development","volume":"8","author":"Zhang","year":"2018","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s10928-019-09626-7","article-title":"Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs","volume":"46","author":"Benet","year":"2019","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"132202","DOI":"10.1016\/j.foodchem.2022.132202","article-title":"Phase \u2160 and phase \u2161 metabolic studies of Citrus flavonoids based on electrochemical simulation and in vitro methods by EC-Q-TOF\/MS and HPLC-Q-TOF\/MS","volume":"380","author":"Yue","year":"2022","journal-title":"Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"473649","DOI":"10.1155\/2013\/473649","article-title":"Liquid Chromatography\/Quadrupole Time-of-Flight Mass Spectrometry for Identification of In Vitro and In Vivo Metabolites of Bornyl Gallate in Rats","volume":"2013","author":"Lan","year":"2013","journal-title":"J. Anal. Methods Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1080\/17460441.2021.1961741","article-title":"An update on the importance of plasma protein binding in drug discovery and development","volume":"16","author":"Di","year":"2021","journal-title":"Expert. Opin. Drug Discov."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1138\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:19:17Z","timestamp":1760033957000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/8\/1138"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":29,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ph18081138"],"URL":"https:\/\/doi.org\/10.3390\/ph18081138","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}