title: Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects.
abstract: In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.
authors.affiliation: Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vizeli
authors.affiliation: Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Schmid
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Prestin
authors.affiliation: Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
authors.forename: Henriette E
authors.initials: HE
authors.lastname: Meyer Zu Schwabedissen
authors.affiliation: Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland. Electronic address: matthias.liechti@usb.ch.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Liechti
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D003430:Cross-Sectional Studies; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006213:Hallucinogens / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D013997:Time Factors; D055815:Young Adult
chemical_list: D006213:Hallucinogens; D015104:3,4-Methylenedioxyamphetamine; D003577:Cytochrome P-450 Enzyme System; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: 3,4-Methylenedioxyamphetamine; 3,4-Methylenedioxymethamphetamine; CYP1A2; CYP2B6; CYP2C19; Pharmacokinetics