{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T18:31:19Z","timestamp":1790447479396,"version":"4.1.0"},"reference-count":74,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"USM Bridging Grant and Smartfund Challenge"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Kratom preparation containing Mitragyna speciosa Korth plant is frequently used as a recreational drug. Mitragynine, a major alkaloid isolated from M. speciosa, is often detected concurrently with other drugs during forensic analysis, indicating a safety concern. P-glycoprotein (P-gp) is a multidrug transporter. Modulation of P-gp transport activity by drugs or herbal compounds in the brain may lead to drug-herb interactions, resulting in neurotoxicity. We aim to determine the effects of mitragynine on the P-gp regulation and possible neurotoxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The effects of mitragynine on the P-gp regulation were investigated in human brain capillary endothelial cells (hCMEC\/D3) using molecular docking and dynamic simulation and an optimized bidirectional transport assay, respectively. Repeated-dose treatment and neurotoxicity assessment were carried out using a blood\u2013brain barrier model and polimerase chain reaction (PCR) array.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key findings<\/jats:title>\n                  <jats:p>Mitragynine inhibits the P-gp transport activity via binding onto the nucleotide-binding domain site and forms a stable interaction with the P-gp protein complex. Nontoxic concentrations of mitragynine (&amp;lt;4 \u03bcM) and substrate drugs (0.001 \u03bcM) in the cells significantly enhanced endothelial cell permeability and elicited signs of neurotoxicity in PC-12 cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Mitragynine is likely a P-gp inhibitor, hence concurrent administration of kratom products with P-gp substrates may lead to clinically significant interactions and neurotoxicity.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jpp\/rgae131","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T18:17:59Z","timestamp":1731608279000},"page":"321-334","source":"Crossref","is-referenced-by-count":1,"title":["The regulatory effects of mitragynine on P-glycoprotein transporter"],"prefix":"10.1093","volume":"77","author":[{"given":"Muhammad Asyraf","family":"Abduraman","sequence":"first","affiliation":[{"name":"Advanced Medical and Dental Institute, Universiti Sains Malaysia , 13200, Kepala Batas, Pulau Pinang ,","place":["Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azimah","family":"Amanah","sequence":"additional","affiliation":[{"name":"Malaysian Institute of Pharmaceuticals and Nutraceuticals, National Institute of Biotechnology Malaysia , 11700, Gelugor, Pulau Pinang ,","place":["Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrul Bariyah Sahul","family":"Hamid","sequence":"additional","affiliation":[{"name":"Advanced Medical and Dental Institute, Universiti Sains Malaysia , 13200, Kepala Batas, Pulau Pinang ,","place":["Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Farris Iman Leong","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Advanced Medical and Dental Institute, Universiti Sains Malaysia , 13200, Kepala Batas, Pulau Pinang ,","place":["Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaida Fariza","family":"Sulaiman","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia , 11800, Pulau Pinang ,","place":["Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6565-699X","authenticated-orcid":false,"given":"Mei Lan","family":"Tan","sequence":"additional","affiliation":[{"name":"Advanced Medical and Dental Institute, Universiti Sains Malaysia , 13200, Kepala Batas, Pulau Pinang ,","place":["Malaysia"]},{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia , 11800, Pulau Pinang ,","place":["Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,11,14]]},"reference":[{"key":"2025020305562947400_CIT0001","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.forsciint.2014.08.011","article-title":"Development of indirect competitive ELISA for quantification of mitragynine in Kratom (Mitragyna speciosa (Roxb.) 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