THE MECHANISM-BASED INACTIVATION OF CYP2D6 BY METHYLENEDIOXYMETHAMPHETAMINE (MDMA)
Heydari A, Rowland Yeo K, Lennard M,
Ellis SW, Tucker G, Rostami-Hodjegan A.
University of Sheffield.
Drug Metab Dispos. 2004 Aug 24
ABSTRACTThe 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 pre-incubation 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 (SE) min(-1) and 12.9 +/- 3.6 (SE) micro M for yeast expressed CYP2D6 and 0.26 +/- 0.02 min(-1) and 14.4 +/- 2.5 micro M, 0.15 +/- 0.01 min(-1) and 8.8 +/- 2.6 micro M, and 0.12 +/- 0.05 min(-1) and 45.3 +/- 32.1 micro M for the three human livers. The rate of inactivation of CYP 2D6 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.P450 (CYP) 2D6
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