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Research ArticleArticle

The Role of Human Hepatic Cytochrome P450 Isozymes in the Metabolism of Racemic 3,4-Methylenedioxy-Methamphetamine and Its Enantiomers

Markus R. Meyer, Frank T. Peters and Hans H. Maurer
Drug Metabolism and Disposition November 2008, 36 (11) 2345-2354; DOI: https://doi.org/10.1124/dmd.108.021543
Markus R. Meyer
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Frank T. Peters
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Hans H. Maurer
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Abstract

The entactogen, 3,4-methylenedioxy-methamphetamine (MDMA), is a chiral drug that is mainly metabolized by N-demethylation and demethylenation. The involvement of cytochrome P450 (P450) isozymes in these metabolic steps has been studied by inhibition assays with human liver microsomes and, in part, with heterologously expressed human P450 isozymes. However, a comprehensive study on the involvement of all relevant human P450s has not been published yet. In addition, the chirality of this drug was not considered in these in vitro studies. The aim of the present work was to study the contribution of human P450 isozymes in the N-demethylation and demethylenation of racemic MDMA and its single enantiomers. MDMA and its enantiomers were incubated using heterologously expressed human P450s, and the metabolites were quantified by gas chromatography-mass spectrometry after derivatization with S-heptafluorobutyrylprolyl chloride. The highest contribution for the N-demethylation as calculated from the enzyme kinetic data, were obtained for CYP2B6 (R,S-MDMA), CYP1A2 (R-MDMA), and CYP2B6 (S-MDMA). In the case of the demethylenation, the isozyme with the highest contribution to net clearance for R,S-MDMA, R-MDMA, and S-MDMA was CYP2D6. For the first time, marked enantioselectivity was observed for N-demethylation and demethylenation by CYP2C19 with a preference for the S-enantiomers. In addition, CYP2D6 showed preference for S-MDMA in the case of demethylenation. None of the other isozymes showed major preferences for certain enantiomers. In conclusion, therefore, the different pharmacokinetic properties of the MDMA enantiomers may be caused by enantioselective metabolism by CYP2C19 and CYP2D6.

Footnotes

  • doi:10.1124/dmd.108.021543.

  • ABBREVIATIONS: MDMA, 3,4-methylenedioxy-methamphetamine; P450, cytochrome P450; DHMA, 3,4-dihydroxymethamphetamine; MDA, 3,4-methylenedioxyamphetamine; DHBA, 3,4-dihydroxybenzylamine; ICM, insect cell microsome; GC, gas chromatography; MS, mass spectrometry; RAF, relative activity factor; TR, turnover rate; PS, probe substrate; HLM, human liver microsome; IS, internal standard; NICI, negative-ion chemical ionization; MAB3A4, monoclonal antibody inhibitory to 3A4; HPLC, high-performance liquid chromatography; SIM, selected-ion monitoring.

    • Received March 20, 2008.
    • Accepted August 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (11)
Drug Metabolism and Disposition
Vol. 36, Issue 11
1 Nov 2008
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Research ArticleArticle

The Role of Human Hepatic Cytochrome P450 Isozymes in the Metabolism of Racemic 3,4-Methylenedioxy-Methamphetamine and Its Enantiomers

Markus R. Meyer, Frank T. Peters and Hans H. Maurer
Drug Metabolism and Disposition November 1, 2008, 36 (11) 2345-2354; DOI: https://doi.org/10.1124/dmd.108.021543

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Research ArticleArticle

The Role of Human Hepatic Cytochrome P450 Isozymes in the Metabolism of Racemic 3,4-Methylenedioxy-Methamphetamine and Its Enantiomers

Markus R. Meyer, Frank T. Peters and Hans H. Maurer
Drug Metabolism and Disposition November 1, 2008, 36 (11) 2345-2354; DOI: https://doi.org/10.1124/dmd.108.021543
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