RT Journal Article
SR Electronic
T1 MECHANISM-BASED INACTIVATION OF CYP2D6 BY METHYLENEDIOXYMETHAMPHETAMINE
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1213
OP 1217
DO 10.1124/dmd.104.001180
VO 32
IS 11
A1 Heydari, A.
A1 Yeo, K. Rowland
A1 Lennard, M. S.
A1 Ellis, S. W.
A1 Tucker, G. T.
A1 Rostami-Hodjegan, A.
YR 2004
UL http://dmd.aspetjournals.org/content/32/11/1213.abstract
AB 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