{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:02:07Z","timestamp":1791475327999,"version":"4.3.4"},"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81841001, 81102752"],"award-info":[{"award-number":["81841001, 81102752"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Major National Science and Technology Program of China for Innovative Drugs","award":["2017ZX09101002-001-002"],"award-info":[{"award-number":["2017ZX09101002-001-002"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Artemisinin-based combination therapies (ACTs) constitute the principal strategy for combating malaria in contemporary times, and research into the multifaceted components of <jats:italic>Artemisia annua<\/jats:italic> L. (<jats:italic>A. annua<\/jats:italic>) has garnered widespread interest among scientists. The aim of this study was to prepare <jats:italic>A. annua<\/jats:italic> extracts (nACTs) and to explore whether nACTs have higher bioavailability and efficacy than artemisinin (ART) alone due to its multiple bioactive components. Initially, the <jats:italic>in vivo<\/jats:italic> antimalarial activity of nACTs was evaluated by two murine malaria models. The results revealed that the antimalarial effect of nACTs was about 10-fold higher than that of ART alone when administered at the same dosage of ART. Then, we analyzed the pharmacokinetic characteristics of nACTs in rat plasma. Remarkably, nACTs exhibited significantly enhanced oral bioavailability, longer half-life as well as extended mean retention time in rats. In addition, the impact of nACTs on P-glycoprotein (P-gp) was evaluated using the Caco-2 cell line. The results showed that both ART and nACTs reduced the efflux rate of the P-gp substrate rhodamine 123 (R123) and induced the expression of P-gp in Caco-2 cells over a range of concentrations. nACTs had certain components-deoxyartemisinin (DEART), artemisinic acid (AA), and dihydroartemisinic acid (DHAA)-that inhibited the efflux and translocation of P-gp and facilitated the reduction of ART efflux. In conclusion, <jats:italic>A. annua<\/jats:italic> extracts significantly improved the antimalarial efficacy and bioavailability compared with ART.<\/jats:p>","DOI":"10.1371\/journal.pone.0322835","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T20:21:27Z","timestamp":1746649287000},"page":"e0322835","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["The plant matrix of Artemisia annua L. for the treatment of malaria: Pharmacodynamic and pharmacokinetic studies"],"prefix":"10.1371","volume":"20","author":[{"given":"Fujie","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohang","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiqiao","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daozeng","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8473-6338","authenticated-orcid":true,"given":"Manyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"issue":"1","key":"pone.0322835.ref001","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12936-023-04452-2","article-title":"Barriers 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Brown","year":"2004","journal-title":"Tetrahedron"},{"issue":"17","key":"pone.0322835.ref039","doi-asserted-by":"crossref","first-page":"4345","DOI":"10.1016\/S0040-4020(98)00148-3","article-title":"A novel endoperoxide and related sesquiterpenes from Artemisia annua which are possibly derived from allylic hydroperoxides","volume":"54","author":"L-K Sy","year":"1998","journal-title":"Tetrahedron"},{"issue":"2","key":"pone.0322835.ref040","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1021\/np50062a020","article-title":"Microbial metabolism studies of the antimalarial sesquiterpene artemisinin","volume":"52","author":"IS Lee","year":"1989","journal-title":"J Nat Prod"},{"issue":"2","key":"pone.0322835.ref041","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.bbrc.2012.01.155","article-title":"Real-time analysis of P-glycoprotein-mediated drug transport across primary intestinal epithelium three-dimensionally cultured in vitro","volume":"419","author":"T Mizutani","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"issue":"11","key":"pone.0322835.ref042","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.trstmh.2012.07.008","article-title":"First-time comparison of the in vitro antimalarial activity of Artemisia annua herbal tea and artemisinin","volume":"106","author":"A De Donno","year":"2012","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"pone.0322835.ref043","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jep.2016.06.041","article-title":"Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria","volume":"190","author":"MR Desrosiers","year":"2016","journal-title":"J Ethnopharmacol"},{"issue":"11","key":"pone.0322835.ref044","doi-asserted-by":"crossref","DOI":"10.1371\/annotation\/57ae25b0-d2c8-444b-ab62-f047c5f3e01e","article-title":"Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract--possible synergistic and resistance mechanisms","volume":"8","author":"JO Suberu","year":"2013","journal-title":"PLoS One"},{"issue":"3","key":"pone.0322835.ref045","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1073\/pnas.1413127112","article-title":"Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin","volume":"112","author":"MA Elfawal","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0322835.ref046","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s11101-010-9166-0","article-title":"Artemisinin production in Artemisia annua: studies in planta and results of a novel delivery method for treating malaria and other neglected diseases","volume":"10","author":"PJ Weathers","year":"2011","journal-title":"Phytochem Rev"},{"issue":"2","key":"pone.0322835.ref047","doi-asserted-by":"crossref","first-page":"128","DOI":"10.4269\/ajtmh.2004.70.128","article-title":"Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood)","volume":"70","author":"K R\u00e4th","year":"2004","journal-title":"Am J Trop Med Hyg"},{"issue":"7","key":"pone.0322835.ref048","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.apjtm.2016.05.004","article-title":"Effects of arteannuin B, arteannuic acid and scopoletin on pharmacokinetics of artemisinin in mice","volume":"9","author":"C Zhang","year":"2016","journal-title":"Asian Pac J Trop Med"},{"issue":"1","key":"pone.0322835.ref049","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0009-9236(03)00092-4","article-title":"Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9","volume":"74","author":"USH Simonsson","year":"2003","journal-title":"Clin Pharmacol Ther"},{"issue":"4","key":"pone.0322835.ref050","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1046\/j.1365-2125.1999.00044.x","article-title":"Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin","volume":"48","author":"US Svensson","year":"1999","journal-title":"Br J Clin Pharmacol"},{"key":"pone.0322835.ref051","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jep.2017.06.025","article-title":"Investigation of the component in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin via regulation of its metabolism","volume":"207","author":"T-Y Cai","year":"2017","journal-title":"J Ethnopharmacol"},{"issue":"1","key":"pone.0322835.ref052","doi-asserted-by":"crossref","DOI":"10.1002\/bmc.4696","article-title":"Quantitative determination of artemisinin in rat hemolyzed plasma by an HPLC-HRMS method","volume":"34","author":"Y Wang","year":"2020","journal-title":"Biomed Chromatogr"},{"issue":"2","key":"pone.0322835.ref053","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1039\/B816679J","article-title":"Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents","volume":"39","author":"D Chaturvedi","year":"2010","journal-title":"Chem Soc Rev"},{"key":"pone.0322835.ref054","doi-asserted-by":"crossref","first-page":"107658","DOI":"10.1016\/j.pharmthera.2020.107658","article-title":"The birth of artemisinin","volume":"216","author":"N Ma","year":"2020","journal-title":"Pharmacol Ther"},{"issue":"1","key":"pone.0322835.ref055","doi-asserted-by":"crossref","first-page":"64","DOI":"10.4269\/ajtmh.2012.11-0817","article-title":"Potential P-glycoprotein-mediated drug-drug interactions of antimalarial agents in Caco-2 cells","volume":"87","author":"EF Oga","year":"2012","journal-title":"Am J Trop Med Hyg"},{"issue":"7","key":"pone.0322835.ref056","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1002\/ptr.7789","article-title":"Antimalarial activity and sensitization of chrysosplenetin against artemisinin-resistant genotype Plasmodium berghei K173 potentially via dual-mechanism of maintaining host P-glycoprotein homeostasis mediated by NF-\u03baB p52 or PXR\/CAR signaling pathways and regulating heme\/haemozoin metabolism","volume":"37","author":"L Wang","year":"2023","journal-title":"Phytother Res"},{"issue":"8","key":"pone.0322835.ref057","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1172\/JCI21682","article-title":"Antimalarial drug resistance","volume":"113","author":"NJ White","year":"2004","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0322835.ref058","article-title":"The interactions of P-glycoprotein with antimalarial drugs, including substrate affinity, inhibition and regulation","volume":"11","author":"SMDKG Senarathna","year":"2016","journal-title":"PLoS One"},{"issue":"1","key":"pone.0322835.ref059","doi-asserted-by":"crossref","first-page":"46","DOI":"10.18433\/J3RC77","article-title":"Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy","volume":"12","author":"T Bansal","year":"2009","journal-title":"J Pharm Pharm 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