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Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics
and toxicity of MDMA
Jiansong Yang1*,
Masound Jamei1,
Amir Heydari2,
Karen Yeo1,
Rafael De La Torre3,
Magi Farre3,
Geoffrey T. Tucker2,
Amin Rostami-Hodjegan2
1 Simcyp Limited, Sheffield, UK.
2 University of Sheffield, Sheffield, UK.
3 Institut Municipal d'Investigació Mèdica, Barcelona, Spain.
* To whom correspondence should be addressed.
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Abstract |
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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
co-administration 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.
Key Words:
ecstasy, inactivation, MDMA, mechanism-based inhibition, modelling
First published on May 19, 2006, doi:10.1177/0269881106065907
Journal of Psychopharmacology 2006;20:842.
A more recent version of this article appeared on November 1, 2006
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