The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans.
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused substituted amphetamine. MDMA is predominantly O-demethylenated in humans by cytochrome P450 isoforms 2D6 and 1A2 (CYP2D6 and CYP CYP1A2, respectively). MDMA is also a mechanism-based inhibitor of CYP2D6. A controlled clinical trial was conducted in 15 healthy male subjects whereby a probe drug, dextromethorphan (DEX), was administered after an oral dose of 1.5 mg/kg MDMA. The pharmacokinetics of DEX and its metabolites were used to evaluate changes in CYP2D6 activity. The urinary metabolic ratio of DEX and dextrorphan was used to calculate a recovery half-life of CYP2D6. After MDMA, DEX Cmax and area under the curve increased approximately 10-fold with corresponding decreases in dextrorphan pharmacokinetic parameters. The metabolic ratio increased almost 100-fold from 0.0061 +/- 0.0056 to 0.4322 +/- 0.2848 after MDMA administration, with 67% of the subjects having a value greater than the antimode of 0.3 for assigning the poor metabolizer phenotype. CYP2D6 activity recovered after 10 days with a recovery half-life of 46.6 hours. In addition to the possible long-term serotonergic effects of MDMA, users must be warned of the consequences of such an inhibition.
O'Mathúna
Brian
B
Human Pharmacology and Clinical Neurosciences Research Group, Neuropsychopharmacology Program, IMIM-Hospital del Mar, Barcelona, Spain.
Farré
Magi
M
Rostami-Hodjegan
Amin
A
Yang
Jiansong
J
Cuyàs
Elisabet
E
Torrens
Marta
M
Pardo
Ricardo
R
Abanades
Sergio
S
Maluf
Silvana
S
Tucker
Geoffrey T
GT
de la Torre
Rafael
R
D000328:Adult; D019540:Area Under Curve; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects* / Q000378:metabolism; D003915:Dextromethorphan / Q000493:pharmacokinetics; D003917:Dextrorphan / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006207:Half-Life; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010641:Phenotype; D010865:Pilot Projects; D013997:Time Factors
D004791:Enzyme Inhibitors; D006213:Hallucinogens; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D018817:N-Methyl-3,4-methylenedioxyamphetamine