Reduced (+/-)-3,4-methylenedioxymethamphetamine ("Ecstasy") metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro

Biochem Pharmacol. 2002 Jun 15;63(12):2111-9. doi: 10.1016/s0006-2952(02)01028-6.

Abstract

"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (+/-)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles (*)2, (*)10, and (*)17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (V(max)/K(m)) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (K(m)). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6(*)2, (*)17, and, particularly, (*)10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.

MeSH terms

  • Alleles
  • Cocaine / pharmacology
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Dextromethorphan / pharmacology
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hallucinogens / metabolism*
  • Humans
  • In Vitro Techniques
  • Microsomes, Liver / metabolism*
  • N-Methyl-3,4-methylenedioxyamphetamine / metabolism*
  • Oxidation-Reduction
  • Recombinant Proteins / metabolism
  • Serotonin Uptake Inhibitors / pharmacology

Substances

  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Hallucinogens
  • Recombinant Proteins
  • Serotonin Uptake Inhibitors
  • Dextromethorphan
  • Cytochrome P-450 CYP2D6
  • Cocaine
  • N-Methyl-3,4-methylenedioxyamphetamine