DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

0090-9556/04/3204-379-381$20.00
DMD 32:379-381, 2004

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Staack, R. F.
Right arrow Articles by Maurer, H. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Staack, R. F.
Right arrow Articles by Maurer, H. H.
SHORT COMMUNICATION

IDENTIFICATION OF HUMAN CYTOCHROME P450 2D6 AS MAJOR ENZYME INVOLVED IN THE O-DEMETHYLATION OF THE DESIGNER DRUG P-METHOXYMETHAMPHETAMINE

Roland F. Staack, Denis S. Theobald, Liane D. Paul, Dietmar Springer, Thomas Kraemer, and Hans H. Maurer

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Homburg (Saar), Germany

p-Methoxymethamphetamine (PMMA) is a new designer drug, listed in many countries as a controlled substance. Several fatalities have been attributed to the abuse of this designer drug. Previous in vivo studies using Wistar rats had shown that PMMA was metabolized mainly by O-demethylation. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of PMMA to p-hydroxymethamphetamine. Baculovirus-infected insect cell microsomes, pooled human liver microsomes (pHLMs), and CYP2D6 poor-metabolizer genotype human liver microsomes (PM HLMs) were used for this purpose. Only CYP2D6 catalyzed O-demethylation. The apparent Km and Vmax values in baculovirus-infected insect cell microsomes were 4.6 ± 1.0 µM and 92.0 ± 3.7 pmol/min/pmol P450, respectively, and 42.0 ± 4.0 µM and 412.5 ± 10.8 pmol/min/mg protein in pHLMs. Inhibition studies with 1 µM quinidine showed significant inhibition of the metabolite formation (67.2 ± 0.6%; p < 0.0001), and comparison of the metabolite formation between pHLMs and PM HLMs revealed significantly lower metabolite formation in the incubations with PM HLMs (87.3 ± 1.1%; p < 0.0001). According to these studies, CYP2D6 is the major P450 involved in O-demethylation of PMMA.

Address correspondence to: Prof. Dr. Hans H. Maurer, Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Building 46, D-66421 Homburg (Saar), Germany. E-mail: hans.maurer{at}uniklinik-saarland.de






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics.