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Received for publication June 25, 2004.
Revised August 19, 2004.
Accepted for publication August 20, 2004.
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 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) 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 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.
Key words:
CNS pharmacokinetics, CYP inhibition, CYP2D, enzyme kinetics, enzyme mechanism, mechanism-based inhibition
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