{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T13:54:06Z","timestamp":1772805246007,"version":"3.50.1"},"reference-count":23,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2011,8,29]],"date-time":"2011-08-29T00:00:00Z","timestamp":1314576000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The extract from Mitragyna speciosa has been widely used as an opium substitute, mainly due to its morphine-like pharmacological effects. This study investigated the effects of M. speciosa alkaloid extract (MSE) on human recombinant cytochrome P450 (CYP) enzyme activities using a modified Crespi method. As compared with the liquid chromatography-mass spectrometry method, this method has shown to be a fast and cost-effective way to perform CYP inhibition studies. The results indicated that MSE has the most potent inhibitory effect on CYP3A4 and CYP2D6, with apparent half-maximal inhibitory concentration (IC50) values of 0.78 \u00b5g\/mL and 0.636 \u00b5g\/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC50 of 39 \u00b5g\/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be determined, however, because inhibition was &lt; 50%. Competitive inhibition was found for the MSE-treated CYP2D6 inhibition assay, whereas non-competitive inhibition was shown in inhibition assays using CYP3A4, CYP1A2 and CYP2C19. Quinidine (CYP2D6), ketoconazole (CYP3A4), tranylcypromine (CYP2C19) and furafylline (CYP1A2) were used as positive controls throughout the experiments. This study shows that MSE may contribute to an herb-drug interaction if administered concomitantly with drugs that are substrates for CYP3A4, CYP2D6 and CYP1A2.<\/jats:p>","DOI":"10.3390\/molecules16097344","type":"journal-article","created":{"date-parts":[[2011,8,30]],"date-time":"2011-08-30T06:04:23Z","timestamp":1314684263000},"page":"7344-7356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay"],"prefix":"10.3390","volume":"16","author":[{"given":"Wai Mun","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia"},{"name":"Aurigene Discovery Technologies (M) Sdn. Bhd, Malaysia, 57000 Bukit Jalil, Kuala Lumpur, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zamri","family":"Chik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murali","family":"Ramachandra","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies Limited, Bangalore 560100, Karnataka, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umarani","family":"Subramaniam","sequence":"additional","affiliation":[{"name":"Aurigene Discovery Technologies (M) Sdn. Bhd, Malaysia, 57000 Bukit Jalil, Kuala Lumpur, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raja Elina Raja","family":"Aziddin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Kuala Lumpur, 50586 Kuala Lumpur, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahurin","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2011,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.tox.2007.06.045","article-title":"In vitro toxicology of extract of Mitragyna speciosa Korth, a Malaysian phytopharmaceutical of abuse","volume":"240","author":"Saidin","year":"2007","journal-title":"Toxicology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1080\/15563650701241795","article-title":"Opioid receptors and legal highs: Salvia divinorum and Kratom","volume":"46","author":"Babu","year":"2008","journal-title":"Clin. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/S0024-3205(98)00075-7","article-title":"Identification of opioid receptor subtypes in antinociceptive action of supraspinal-administered mitragynine in mice","volume":"62","author":"Thongpradichote","year":"1998","journal-title":"Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jep.2007.11.032","article-title":"Inhibitory effects of kratom leaf extract (Mitragyna speciosa Korth.) on the rat gastrointestinal tract","volume":"116","author":"Chittrakarn","year":"2008","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","first-page":"972","article-title":"Limited applicability of 7-methoxy-4-trifluoromethylcoumarin as a CYP2C9-selective substrate","volume":"60","author":"Porrogi","year":"2008","journal-title":"Pharmacol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"490","DOI":"10.3923\/ijp.2010.494.499","article-title":"Evaluation of selected Malaysian medicinal plants on phase I drug metabolizing enzymes, CYP2C9, CYP2D6 and CYP3A4 activities in vitro","volume":"6","author":"Hanapi","year":"2010","journal-title":"Int. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/08998280.2000.11927719","article-title":"Drug interactions due to cytochrome P450","volume":"13","author":"Ogu","year":"2000","journal-title":"Proc. Bay. Univ. Med. Cent"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1124\/dmd.31.7.945","article-title":"Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes","volume":"31","author":"Ito","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_9","unstructured":"U.S. Food and Drug Administration (2011, August 19). Guidance for Industry: Drug Metabolism\/Drug Interaction Studies in the Drug Development Process: Studies in Vitro, Available online: http:\/\/www.fda.gov\/cder\/guidance.htm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1208\/s12248-008-9042-7","article-title":"In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: Current status on methodologies and their utility for predicting drug-drug interactions","volume":"10","author":"Fowler","year":"2008","journal-title":"AAPS J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1006\/abio.1997.2145","article-title":"Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450","volume":"248","author":"Crespi","year":"1997","journal-title":"Anal. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1080\/004982598238886","article-title":"Inhibition and induction of human cytochrome P450 (CYP) enzymes","volume":"28","author":"Pelkonen","year":"1998","journal-title":"Xenobiotica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1124\/dmd.32.7.699","article-title":"Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes","volume":"32","author":"Donato","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/S0024-3205(02)01913-6","article-title":"Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity","volume":"71","author":"Zou","year":"2002","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"198","DOI":"10.6026\/97320630003198","article-title":"Pharmacovigilance: Effects of herbal components on human drugs interactions involving cytochrome P450","volume":"3","author":"Saxena","year":"2008","journal-title":"Bioinformation"},{"key":"ref_16","first-page":"39","article-title":"Effects of the extracts from Mitragyna speciosa Korth. Leaves on analgesic and behavioral activities in experimental animals","volume":"29","author":"Reanmongkol","year":"2007","journal-title":"Songklanakarin J. Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"357","DOI":"10.36076\/ppj.2007\/10\/357","article-title":"Drug-related side effects of long-term intrathecal morphine therapy","volume":"10","author":"Ruan","year":"2007","journal-title":"Pain Physician"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1016\/j.lfs.2003.09.054","article-title":"Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa","volume":"74","author":"Matsumoto","year":"2004","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1002\/jms.1607","article-title":"Studies on the metabolism of mitragynine, the main alkaloid of the herbal drug Kratom, in rat and human urine using liquid chromatography-linear ion trap mass spectrometry","volume":"44","author":"Philipp","year":"2009","journal-title":"J. Mass Spectrom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1111\/j.2042-7158.1965.tb07599.x","article-title":"Alkaloids from Mitragyna speciosa Korth","volume":"17","author":"Beckett","year":"1965","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1042\/bj1370143","article-title":"A simple graphical method for determining the inhibition constants of mixed uncompetitive and non-competitive inhibitors","volume":"137","year":"1974","journal-title":"Biochem. J."},{"key":"ref_22","first-page":"349","article-title":"St John\u2019s wort (Hypericum perforatum): Drug interactions and clinical outcomes","volume":"54","author":"Henderson","year":"2002","journal-title":"J. Clin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3390\/molecules15010432","article-title":"In vitro and in vivo effects of three different Mitragyna speciosa Korth leaf extracts on phase II drug metabolizing enzymes\u2014glutathione transferases (GSTs)","volume":"15","author":"Azizi","year":"2010","journal-title":"Molecules"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/16\/9\/7344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:57:13Z","timestamp":1760219833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/16\/9\/7344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,8,29]]},"references-count":23,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2011,9]]}},"alternative-id":["molecules16097344"],"URL":"https:\/\/doi.org\/10.3390\/molecules16097344","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,8,29]]}}}