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 (k_inact and K_I), 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.