![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Academic Unit of Clinical Pharmacology, Pharmacokinetics & Pharmacogenetics Group, Division of Clinical Sciences (South), University of Sheffield, United Kingdom (A.H., M.S.L., S.W.E., G.T.T., A.R.-H); and Simcyp Limited, Blades Enterprise Centre, Sheffield, United Kingdom (K.R.Y., G.T.T., A.R.-H.)
The potency of methylenedioxymethamphetamine (MDMA) as a mechanism-based inhibitor of CYP2D6 has been defined using microsomes prepared from yeast expressing the enzyme and from three human livers. The inhibitory effect was increased by preincubation through formation of a metabolic intermediate complex. Inactivation parameters (kinact and KI), defined with respect to the O-demethylation of dextromethorphan, were 0.29 ± 0.03 (S.E.) min-1 and 12.9 ± 3.6 (S.E.) µM for yeast-expressed CYP2D6, and 0.26 ± 0.02 min-1 and 14.4 ± 2.5 µM, 0.15 ± 0.01 min-1 and 8.8 ± 2.6 µM, and 0.12 ± 0.05 min-1 and 45.3 ± 32.1 µM for the liver microsomal preparations. The rate of inactivation of CYP2D6 by MDMA decreased when quinidine, a competitive inhibitor of CYP2D6, was added to the primary incubation mixture. However, inactivation was unaffected by the addition of glutathione. The results indicate that MDMA is a potent mechanism-based inhibitor of CYP2D6, with implications for understanding its in vivo disposition and drug interaction potential.
This article has been cited by other articles:
|
|
 |
|
  M. Farre, S. Abanades, P. N. Roset, A. M. Peiro, M. Torrens, B. O'Mathuna, M. Segura, and R. de la Torre Pharmacological Interaction between 3,4-Methylenedioxymethamphetamine (Ecstasy) and Paroxetine: Pharmacological Effects and Pharmacokinetics J. Pharmacol. Exp. Ther., December 1, 2007; 323(3): 954 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Obach, R. L. Walsky, and K. Venkatakrishnan Mechanism-Based Inactivation of Human Cytochrome P450 Enzymes and the Prediction of Drug-Drug Interactions Drug Metab. Dispos., February 1, 2007; 35(2): 246 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Van, A. Heydari, J. Yang, J. Hargreaves, K. Rowland-Yeo, M. S. Lennard, G. T. Tucker, and A. Rostami-Hodjegan The impact of experimental design on assessing mechanism-based inactivation of CYP2D6 by MDMA (Ecstasy) J Psychopharmacol, November 1, 2006; 20(6): 834 - 841. [Abstract] [PDF]
|
|
|
|
|
|
J. Yang, M. Jamei, A. Heydari, K. R. Yeo, R. de la Torre, M. Farre, G. T. Tucker, and A. Rostami-Hodjegan Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA J Psychopharmacol, November 1, 2006; 20(6): 842 - 849. [Abstract] [PDF]
|
|
|
|
|
|
K. A. Usmani, T. M. Cho, R. L. Rose, and E. Hodgson Inhibition of the Human Liver Microsomal and Human Cytochrome P450 1A2 and 3A4 Metabolism of Estradiol by Deployment-Related and Other Chemicals Drug Metab. Dispos., September 1, 2006; 34(9): 1606 - 1614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Easton and C. A. Marsden Ecstasy: Are animal data consistent between species and can they translate to humans? J Psychopharmacol, March 1, 2006; 20(2): 194 - 210. [Abstract] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
