Mechanism-based inactivation of CYP2D6 by methylenedioxymethamphetamine.
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.) microM for yeast-expressed CYP2D6, and 0.26 +/- 0.02 min(-1) and 14.4 +/- 2.5 microM, 0.15 +/- 0.01 min(-1) and 8.8 +/- 2.6 microM, and 0.12 +/- 0.05 min(-1) and 45.3 +/- 32.1 microM 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.
Division of Clinical Sciences (South), University of Sheffield, UK.
A
A
Heydari
K Rowland
KR
Yeo
M S
MS
Lennard
S W
SW
Ellis
G T
GT
Tucker
A
A
Rostami-Hodjegan
D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D019389:Cytochrome P-450 CYP2D6; D018817:N-Methyl-3,4-methylenedioxyamphetamine