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Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay
Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
Aurigene Discovery Technologies (M) Sdn. Bhd, Malaysia, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
Aurigene Discovery Technologies Limited, Bangalore 560100, Karnataka, India
Department of Pathology, Hospital Kuala Lumpur, 50586 Kuala Lumpur, Malaysia
* Author to whom correspondence should be addressed.
Received: 4 July 2011; in revised form: 8 August 2011 / Accepted: 19 August 2011 / Published: 29 August 2011
(This article belongs to the Special Issue Alkaloids
Abstract: 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 µg/mL and 0.636 µg/mL, respectively. In addition, moderate inhibition was observed for CYP1A2, with an IC50 of 39 µg/mL, and weak inhibition was detected for CYP2C19. The IC50 of CYP2C19 could not be determined, however, because inhibition was < 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.
Keywords: herb-drug interactions; cytochrome P450 (CYP); Mitragyna speciosa; in vitro; alkaloids
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Kong, W.M.; Chik, Z.; Ramachandra, M.; Subramaniam, U.; Aziddin, R.E.R.; Mohamed, Z. Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay. Molecules 2011, 16, 7344-7356.
Kong WM, Chik Z, Ramachandra M, Subramaniam U, Aziddin RER, Mohamed Z. Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay. Molecules. 2011; 16(9):7344-7356.
Kong, Wai Mun; Chik, Zamri; Ramachandra, Murali; Subramaniam, Umarani; Aziddin, Raja Elina Raja; Mohamed, Zahurin. 2011. "Evaluation of the Effects of Mitragyna speciosa Alkaloid Extract on Cytochrome P450 Enzymes Using a High Throughput Assay." Molecules 16, no. 9: 7344-7356.