Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA
Jiansong Yang, Masoud Jamei, Amir Heydari, Karen Rowland Yeo, Rafael de la Torre, Magı́ Farré, Geoffrey T. Tucker, Amin Rostami‐hodjegan
Journal of Psychopharmacology May 20, 2006 DOI: 10.1177/0269881106065907 via OpenAlex
Summary
AI-generated from the abstractA physiologically-based model of drug metabolism predicted that a typical recreational dose of MDMA (ecstasy) inactivates most hepatic CYP2D6 within an hour, and that recovery to basal CYP2D6 levels takes at least 10 days. The analysis suggests that genetic polymorphism of CYP2D6 and coadministration of CYP2D6 inhibitors may have less impact on MDMA's pharmacokinetics and acute toxicity risk than previously thought, consistent with clinical observations showing no obvious link between inherited CYP2D6 deficiency and acute MDMA intoxication.
Study at a glance
| Characteristics | Modeling study Peer reviewed |
|---|---|
| Dose | a typical recreational MDMA dose |
| Topics | MDMA |
| Keywords | Cyp2d6 Pharmacology Pharmacokinetics |
| Citations | 89 |
| Key finding | A typical recreational MDMA dose could inactivate most hepatic CYP2D6 within an hour, with recovery taking at least 10 days, suggesting genetic polymorphism and CYP2D6 inhibitors have less impact on MDMA pharmacokinetics and acute toxicity than previously thought. |
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.