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

Yamini Ramamoorthy, Aiming Yu, Nina Suh, Robert L. Haining, Rachel F. Tyndale, Edward M. Sellers

Research output: Contribution to journalArticle

57 Scopus citations

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 (Vmax/Km) 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 (Km). 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.

Original languageEnglish (US)
Pages (from-to)2111-2119
Number of pages9
JournalBiochemical Pharmacology
Volume63
Issue number12
DOIs
StatePublished - Jun 15 2002
Externally publishedYes

Keywords

  • (±)-3,4-Methylenedioxymethamphetamine
  • Cytochrome P450 2D6
  • Drug interactions
  • Drug metabolism
  • Pharmacogenetics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology

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