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Drug Metabolism and Disposition Fast Forward
First published on June 2, 2005; DOI: 10.1124/dmd.105.003772

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Received for publication January 25, 2005.
Revised May 4, 2005.
Accepted for publication May 27, 2005.

Role of CYP2E1 in deramciclane metabolism

Katalin Monostory 1*, Krisztina Kohalmy 1, Eszter Hazai 1, Laszlo Vereczkey 1, Laszlo Kobori 2

1 Chemical Research Center, Hungarian Academy of Sciences 2 Transplantation and Surgery Clinic, Semmelweis University

* Address correspondence to: E-mail: monostor{at}chemres.hu

Abstract

The aim of our study was to identify the form(s) of cytochrome P450 responsible for the metabolism of deramciclane, a new anxiolytic drug candidate. The main routes of biotransformation in hepatic microsomes were side chain modification (N-demethylation or total side chain cleavage) and hydroxylation at several points of the molecule. Although several cytochrome P450 forms were involved in the metabolism, the role of CYP2E1 should be emphasized, since it catalyzed almost all steps. Production of deramciclane metabolites was significantly inhibited by diethyl-dithiocarbamate and was elevated in liver microsomes of isoniazid-treated rats. Furthermore, cDNA-expressed rat CYP2E1 generated the metabolites formed by side chain modification and hydroxylation. Neither deramciclane nor its primary metabolite, N-desmethyl deramciclane were able to influence directly the activity of CYP2E1. However, during the biotransformation, one or more metabolites must have been formed which were potent inhibitors of CYP2E1.


Key words: CYP2E, inhibition, liver microsomes




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