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First published on November 4, 2005; DOI: 10.1124/dmd.105.006445

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Received for publication July 5, 2005.
Revised November 2, 2005.
Accepted for publication November 2, 2005.

Characterization of human cytochrome P-450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine

Jacek Wojcikowski 1*, Patrick Maurel 2, Wladyslawa Anna Daniel 1

1 Polish Academy of Sciences, Institute of Pharmacology 2 INSERM U632, Hepatic Physiopathology

* Address correspondence to: E-mail: wojcikow{at}if-pan.krakow.pl

Abstract

The aim of the present study was to identify human cytochrome P-450 enzymes (CYPs) involved in mono-2-, di-2- and 5-sulphoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human CYPs (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulphoxidation and N-demethylation (34-52%), while CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulphoxidation of thioridazine in the human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulphoxidation (22%). Therefore the sulphoridazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demetylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulphoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic {alpha}1 receptor blocking properties of mono-2- and di-2-sulphoxides, the obtained results are of pharmacological and clinical importance, in particular in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper co-administered drug and dosage) to avoid undesirable drug interactions.


Key words: CYP inhibition, cytochrome P450 isoforms, enzyme kinetics, human CYP enzymes, liver microsomes, metabolite kinetics


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