The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans

• Published in: Journal of clinical psychopharmacology Vol. 28; no. 5; p. 523
• Main Authors: O'Mathúna, Brian, Farré, Magi, Rostami-Hodjegan, Amin, Yang, Jiansong, Cuyàs, Elisabet, Torrens, Marta, Pardo, Ricardo, Abanades, Sergio, Maluf, Silvana, Tucker, Geoffrey T, de la Torre, Rafael
• Format: Journal Article
• Language: English
• Published: United States 01.10.2008
• Subjects: Adult; Area Under Curve; Cytochrome P-450 CYP2D6 - drug effects; Cytochrome P-450 CYP2D6 - metabolism; Dextromethorphan - pharmacokinetics; Dextrorphan - pharmacokinetics; Enzyme Inhibitors - pharmacology; Half-Life; Hallucinogens - pharmacology; Humans; Male; N-Methyl-3,4-methylenedioxyamphetamine - pharmacology; Phenotype; Pilot Projects; Time Factors
• DOI: 10.1097/JCP.0b013e318184ff6e

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.