TY - JOUR
T1 - The consequences of 3,4-methylenedioxymethamphetamine induced CYP2D6 inhibition in humans
AU - O'Mathúna, Brian
AU - Farré, Magi
AU - Rostami-Hodjegan, Amin
AU - Yang, Jiansong
AU - Cuyàs, Elisabet
AU - Torrens, Marta
AU - Pardo, Ricardo
AU - Abanades, Sergio
AU - Maluf, Silvana
AU - Tucker, Geoffrey T.
AU - De La Torre, Rafael
PY - 2008/10
Y1 - 2008/10
N2 - 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. Copyright © 2008 by Lippincott Williams & Wilkins.
AB - 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. Copyright © 2008 by Lippincott Williams & Wilkins.
U2 - 10.1097/JCP.0b013e318184ff6e
DO - 10.1097/JCP.0b013e318184ff6e
M3 - Article
SN - 0271-0749
VL - 28
SP - 525
EP - 531
JO - Journal of Clinical Psychopharmacology
JF - Journal of Clinical Psychopharmacology
IS - 5
ER -