TY - JOUR T1 - MECHANISM-BASED INACTIVATION OF CYP2D6 BY METHYLENEDIOXYMETHAMPHETAMINE JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1213 LP - 1217 DO - 10.1124/dmd.104.001180 VL - 32 IS - 11 AU - A. Heydari AU - K. Rowland Yeo AU - M. S. Lennard AU - S. W. Ellis AU - G. T. Tucker AU - A. Rostami-Hodjegan Y1 - 2004/11/01 UR - http://dmd.aspetjournals.org/content/32/11/1213.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -