MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

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.

Dose‐Response Pharmacological Study of Mephedrone and Its Metabolites: Pharmacokinetics, Serotoninergic Effects, and Impact of CYP2D6 Genetic Variation

“…5,27 The considerable difference in MEPH bioavailability may obscure the effects attributable to CYP2D6 and its relevance in acute intoxication cases should be tuned down. 28 Our study has strengths and limitations. The main limitation is the number of participants, although findings regarding the impact Table S1 for details): (a) Individual data of MEPH AUC 0-8 h for subjects with an activity score of >2 or 2 and those with an activity score of ≤1.5 (in gray for activity score = 1.5 and in black for an activity score = 1) carrying decreased and/or no function alleles.…”

Effects of Electroacupuncture on Methamphetamine‐Induced Behavioral Changes in Mice

“…Previously, a gene knockout study suggests that phenylethylamine is majorly metabolized by MAO-B in the rodent [30]. METH might be decomposed into amphetamine by cytochrome P-450s [31] and acute amphetamine administration increased phenylethylamine level in the rodent's brain which was also demonstrated in an early study [32]. Hence, there exists a possible mechanism that chronic METH administration caused increases of amphetamine and subsequently raised phenylethylamine concentration in brain.…”

Asians compared to Whites show increased response to d-amphetamine on select subjective and cardiovascular measures

“…While these initial findings should be treated as preliminary until replicated, prior genetic studies suggest that these effects are biologically plausible: Asians are more likely to possess SLC6A3 and CYP2D6 genotype or allele variants that may increase sensitivity to amphetamine effects (de la Torre et al , 2012, Kang et al , 1999, Lott et al , 2005). However, the current study did not directly assess genotype, and future work is needed to understand how inter-racial genetic differences might underlie differences in subjective and cardiovascular drug response.…”