{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T03:19:15Z","timestamp":1764645555403,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Payap University and The Nagai Foundation Tokyo","award":["PRE-DOCTORAL SCHOLARSHIP 2014"],"award-info":[{"award-number":["PRE-DOCTORAL SCHOLARSHIP 2014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The capacity of \u03b1-mangostin (\u03b1-MG) and \u03b2-mangostin (\u03b2-MG) from mangosteen pericarp on P-glycoprotein (Pgp) in silico, in vitro, and ex vivo was investigated in this study. Screening with the ADMET Predictor\u2122 program predicted the two compounds to be both a Pgp inhibitor and Pgp substrate. The compounds tended to interact with Pgp and inhibit Pgp ATPase activity. Additionally, bidirectional transport on Caco-2 cell monolayers demonstrated a significantly lower efflux ratio than that of the control (\u03b1-(44.68) and \u03b2-(46.08) MG versus the control (66.26); p &lt; 0.05) indicating an inhibitory effect on Pgp activity. Test compounds additionally revealed a downregulation of MDR1 mRNA expression. Moreover, an ex vivo absorptive transport in everted mouse ileum confirmed the previous results that \u03b1-MG had a Pgp affinity inhibitor, leading to an increase in absorption of the Pgp substrate in the serosal side. In conclusion, \u03b1- and \u03b2-MG have the capability to inhibit Pgp and they also alter Pgp expression, which makes them possible candidates for reducing multidrug resistance. Additionally, they influence the bioavailability and transport of Pgp substrate drugs.<\/jats:p>","DOI":"10.3390\/molecules25245877","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:45:36Z","timestamp":1607906736000},"page":"5877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Intestinal Efflux Transporter Inhibition Activity of Xanthones from Mangosteen Pericarp: An In Silico, In Vitro and Ex Vivo Approach"],"prefix":"10.3390","volume":"25","author":[{"given":"Panudda","family":"Dechwongya","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevi, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songpol","family":"Limpisood","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevi, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nawong","family":"Boonnak","sequence":"additional","affiliation":[{"name":"Department of Basic Science and Mathematics, Faculty of Science, Thaksin University, Muang Songkhla, Songkhla 90000, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3223-1551","authenticated-orcid":false,"given":"Supachoke","family":"Mangmool","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Rajathevi, Bangkok 10400, Thailand"},{"name":"Department of Pharmacology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6796-5163","authenticated-orcid":false,"given":"Mariko","family":"Takeda-Morishita","sequence":"additional","affiliation":[{"name":"Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Hyogo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0375-0144","authenticated-orcid":false,"given":"Thitianan","family":"Kulsirirat","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevi, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pattarawit","family":"Rukthong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, Srinakarinwirot University, Nakornnayok 26120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1276-9266","authenticated-orcid":false,"given":"Korbtham","family":"Sathirakul","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Rajathevi, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1002\/ptr.2730","article-title":"Garcinia mangostana L.: A phytochemical and pharmacological review","volume":"23","author":"Obolskiy","year":"2009","journal-title":"Phytother. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.fct.2017.08.021","article-title":"Medicinal properties of mangosteen (Garcinia mangostana L.): A comprehensive update","volume":"109","year":"2017","journal-title":"Food Chem. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.arabjc.2014.02.011","article-title":"\u03b1-Mangostin from Garcinia mangostana Linn: An updated review of its pharmacological properties","volume":"9","author":"Ibrahim","year":"2016","journal-title":"Arab. J. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.jtcme.2018.01.006","article-title":"Usage, biological activity, and safety of selected botanical dietary supplements consumed in the United States","volume":"8","author":"Benatrehina","year":"2018","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1146\/annurev.biochem.71.102301.093055","article-title":"Mammalian ABC transporters in health and disease","volume":"71","author":"Borst","year":"2002","journal-title":"Annu. Rev. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/BF00689638","article-title":"P-glycoprotein, multidrug resistance and tumor progression","volume":"13","author":"Bradley","year":"1994","journal-title":"Cancer Metastasis Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1021\/mp049921x","article-title":"Impact of P-Glycoprotein-Mediated Intestinal Efflux Kinetics on Oral Bioavailability of P-Glycoprotein Substrates","volume":"1","author":"Kwon","year":"2004","journal-title":"Mol. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1124\/dmd.111.044008","article-title":"Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora","volume":"40","author":"Yang","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1021\/mp400450m","article-title":"ADMET Evaluation in Drug Discovery. 13. Development of in Silico Prediction Models for P-Glycoprotein Substrates","volume":"11","author":"Li","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"14991","DOI":"10.1016\/S0021-9258(18)82429-2","article-title":"Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells","volume":"298","author":"Hunter","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s11418-018-1222-x","article-title":"Use of a Caco-2 permeability assay to evaluate the efects of several Kampo medicines on the drug transporter P-glycoprotein","volume":"72","author":"Matsumoto","year":"2018","journal-title":"J. Nat. Med."},{"key":"ref_12","first-page":"3157","article-title":"Everted rat intestinal sacs: A newmodel for the quantitation of P-glycoprotein mediated-efflux ofanticancer agents","volume":"20","author":"Duncan","year":"2000","journal-title":"Anticancer. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.2042-7158.2011.01391.x","article-title":"Everted gut sac model as a tool in pharmaceutical research: Limitations and applications","volume":"64","author":"Alam","year":"2012","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1056-8719(00)00109-X","article-title":"Progress in predicting human ADME parameters in silico","volume":"44","author":"Ekins","year":"2000","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.drudis.2011.11.003","article-title":"Computational models for predicting substrates or inhibitors of P-glycoprotein","volume":"17","author":"Chen","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1021\/jm701122q","article-title":"Generation of a Set of Simple, Interpretable ADMET Rules of Thumb","volume":"51","author":"Gleeson","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/clpt.2012.164","article-title":"Computational modeling to accelerate the identification of substrates and inhibitors for transporters that affect drug disposition","volume":"92","author":"Ekins","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107621","DOI":"10.1016\/j.pharmthera.2020.107621","article-title":"Phytocannabinoid drug-drug interactions and their clinical implications","volume":"215","author":"Silva","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1007\/s00044-012-0203-y","article-title":"Bioactive xanthones with effect on P-glycoprotein and prediction of intestinal absorption","volume":"22","author":"Sousa","year":"2012","journal-title":"Med. Chem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ejmech.2015.01.006","article-title":"Xanthone analogues as potent modulators of intestinal P-glycoprotein","volume":"93","author":"Chae","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Martins, E., Silva, V., Lemos, A., Palmeira, A., Puthongking, P., De Sousa, M.E., Rocha-Pereira, C., Ghanem, C.I., Carmo, H., and Remi\u00e3o, F. (2019). Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies. Molecules, 24.","DOI":"10.3390\/molecules24040707"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.13057\/nusbiosci\/n110109","article-title":"Ethanolic extract of mangosteen (Garcinia mangostana) pericarp as sensitivity enhancer of doxorubicin on MCF-7 cells by inhibiting P-glycoprotein","volume":"11","author":"Laksmiani","year":"2019","journal-title":"Nusant. Biosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.bcp.2016.08.013","article-title":"Cooperativity between verapamil and ATP bound to the efflux transporter P-glycoprotein","volume":"118","author":"Ledwitch","year":"2016","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-19325-x","article-title":"Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells","volume":"8","author":"Nanayakkara","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_25","unstructured":"Borchardt, R., Kerns, E., Lipinski, C., Thakker, D., and Wang, B. (2004). Cultured Epithelial Cell Assays Used to Estimate Intestinal Absorption Potential. Pharmaceutical Profiling in Drug Discovery for Lead Selection, AAPS Press."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1254\/jjp.71.337","article-title":"The Mode of Inhibitory Action of alpha-Mangostin, a Novel Inhibitor, on the Sarcoplasmic Reticulum Ca(2+)-Pumping ATPase from Rabbit Skeletal Muscle","volume":"71","author":"Furukawa","year":"1996","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_27","unstructured":"Edward, H., and Kerns, L.D. (2008). In Vitro Transporter Methods. Drug-Like Properties: Concepts, Structure Design and Methods: From ADME to Toxicity Optimization, Academic Press."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"675","DOI":"10.3945\/jn.111.156992","article-title":"Xanthones in Mangosteen Juice Are Absorbed and Partially Conjugated by Healthy Adults","volume":"142","author":"Chitchumroonchokchai","year":"2012","journal-title":"J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/jf4004434","article-title":"Alpha-Mangostin: Anti-Inflammatory Activity and Metabolism by Human Cells","volume":"61","author":"Chitchumroonchokchai","year":"2013","journal-title":"J. Agric. Food Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s13318-018-0474-x","article-title":"Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration","volume":"43","author":"Matzneller","year":"2018","journal-title":"Eur. J. Drug Metab. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1002\/mnfr.201000511","article-title":"Pharmacokinetics of \u03b1-mangostin in rats after intravenous and oral application","volume":"55","author":"Li","year":"2011","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"127494","DOI":"10.1016\/j.bmcl.2020.127494","article-title":"Modified tetra-oxygenated xanthones analogues as anti-MRSA and P. aeruginosa agent and their synergism with vancomycin","volume":"30","author":"Boonnak","year":"2020","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1080\/1062936X.2014.976265","article-title":"Computational classification models for predicting the interaction of drugs with P-glycoprotein and breast cancer resistance protein","volume":"25","author":"Zloh","year":"2014","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0169-409X(02)00170-9","article-title":"In vitro and in vivo models for assessing drug efflux transporter activity","volume":"55","author":"Zhang","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1080\/10611860310001648248","article-title":"Classification Analysis of P-Glycoprotein Substrate Specificity","volume":"11","author":"Didziapetris","year":"2003","journal-title":"J. Drug Target."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1021\/jm101421d","article-title":"A Novel Approach for Predicting P-Glycoprotein (ABCB1) Inhibition Using Molecular Interaction Fields","volume":"54","author":"Broccatelli","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_37","unstructured":"(2014, January 20). Pgp-Glo\u2122 Assay System: Instruction for Use of Products V3591 and V3601. Madison: Promega Corporation. Available online: www.promega.com."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2133\/dmpk.DMPK-12-NT-024","article-title":"Studies on the intestinal absorption characteristics of sulfasalazine, a breast cancer resistance protein (BCRP) substrate","volume":"28","author":"Tomaru","year":"2012","journal-title":"Drug Metab. Pharm."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/24\/5877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:44:08Z","timestamp":1760179448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/24\/5877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,11]]},"references-count":38,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["molecules25245877"],"URL":"https:\/\/doi.org\/10.3390\/molecules25245877","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2020,12,11]]}}}