title: Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA.
abstract: The aim of this study was to model the in vivo kinetic consequences of mechanism-based inhibition (MBI) of CYP2D6 by 3,4 methylenedioxymethamphetamine (MDMA, ecstasy). A model with physiologically-based components of drug metabolism was developed, taking account of change in the hepatic content of active CYP2D6 due to MBI by MDMA. Based on the in vitro information, plasma concentration time profiles of MDMA after various doses were computed and compared with reported observations. The analysis suggested that a typical recreational MDMA dose could inactivate most hepatic CYP2D6 within an hour, and the return to a basal level of CYP2D6 could take at least 10 days. Thus, the genetic polymorphism of CYP2D6 and coadministration of CYP2D6 inhibitors may have less impact on MDMA pharmacokinetics and the risk of acute toxicity than previously thought. This is consistent with clinical observations that indicate no obvious link between inherited CYP2D6 deficiency and acute MDMA intoxication.
authors.affiliation: Simcyp Limited, Sheffield, UK. J.Yang@simcyp.com
authors.forename: Jiansong
authors.initials: J
authors.lastname: Yang
authors.forename: Masoud
authors.initials: M
authors.lastname: Jamei
authors.forename: Amir
authors.initials: A
authors.lastname: Heydari
authors.forename: Karen R
authors.initials: KR
authors.lastname: Yeo
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.forename: Magí
authors.initials: M
authors.lastname: Farré
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Tucker
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D000465:Algorithms; D019540:Area Under Curve; D003198:Computer Simulation; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003640:Dealkylation; D004791:Enzyme Inhibitors; D005838:Genotype; D006213:Hallucinogens / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D007700:Kinetics; D015233:Models, Statistical; D008970:Molecular Weight; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D006213:Hallucinogens; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D018817:N-Methyl-3,4-methylenedioxyamphetamine