Abstract
In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies.
Highlights
Amphetamine-type stimulants (ATS) make up a group of substances comprised of synthetic stimulants including amphetamine, methamphetamine, methcathinone, and ecstasygroup substances [e.g., 3,4-methylenedioxymethamphetamine (MDMA) and its analogues]
CONCLUDING REMARKS The involvement of CYP2D6 polymorphism in the metabolic clearance of both MDMA and methamphetamine leads to the speculation that it should have an impact on acute and long-term drug toxicity and drug taking behavior
Concerning acute effects, those subject carriers of alleles with a reduced functionality are at higher risk, for both MDMA and methamphetamine, of experiencing heightened pharmacological effects
Summary
Amphetamine-type stimulants (ATS) make up a group of substances comprised of synthetic stimulants including amphetamine, methamphetamine, methcathinone, and ecstasygroup substances [e.g., 3,4-methylenedioxymethamphetamine (MDMA) and its analogues]. Due to the fact that ATS are a broad class of compounds encompassing a number of substances, and that scant in vivo data from human studies are available for most of them (Wu et al, 1997), the review will focus mainly on the following two: MDMA (ecstasy) and methamphetamine They will serve as archetypes in order to discuss the translation and clinical significance of in vitro to in vivo findings. An in vitro study comparing catalytically the CYP2D6*10 allelic variant vs CYP2D6*1 (wild type), which is more prevalent in Caucasians, showed that the ratios of intrinsic clearance (Vmax/Km) of *1 to *10 for MDMA O-demethylenation was 123, and for methamphetamine 67, for the p-hydroxylation 157 of the N-demethylation (Ramamoorthy et al, 2001) This almost 100-fold difference in intrinsic clearance for both drugs, depending on the allelic variant considered, is of significance in the interpretation of clinical data. Preliminary in vitro studies showing that MDMA was a CYP2D6 substrate raised the possibility that subject carriers www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
