@article {Heydari1213, author = {A. Heydari and K. Rowland Yeo and M. S. Lennard and S. W. Ellis and G. T. Tucker and A. Rostami-Hodjegan}, title = {MECHANISM-BASED INACTIVATION OF CYP2D6 BY METHYLENEDIOXYMETHAMPHETAMINE}, volume = {32}, number = {11}, pages = {1213--1217}, year = {2004}, doi = {10.1124/dmd.104.001180}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 {\textpm} 0.03 (S.E.) min-1 and 12.9 {\textpm} 3.6 (S.E.) μM for yeast-expressed CYP2D6, and 0.26 {\textpm} 0.02 min-1 and 14.4 {\textpm} 2.5 μM, 0.15 {\textpm} 0.01 min-1 and 8.8 {\textpm} 2.6 μM, and 0.12 {\textpm} 0.05 min-1 and 45.3 {\textpm} 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/32/11/1213}, eprint = {https://dmd.aspetjournals.org/content/32/11/1213.full.pdf}, journal = {Drug Metabolism and Disposition} }