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Drug Metabolism and Disposition Fast Forward
First published on November 4, 2005; DOI: 10.1124/dmd.105.006445

0090-9556/06/3403-471-476$20.00
DMD 34:471-476, 2006

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CHARACTERIZATION OF HUMAN CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF THE PIPERIDINE-TYPE PHENOTHIAZINE NEUROLEPTIC THIORIDAZINE

Jacek Wójcikowski, Patrick Maurel, and Wladyslawa A. Daniel

Polish Academy of Sciences, Institute of Pharmacology, Kraków, Poland (J.W., W.A.D.); and INSERM, U632, F-3493 Montpellier, France; Univ. Montpellier-I, Montpellier, F-34000 France (P.M.)

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34–52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/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-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic {alpha}1 receptor-blocking properties of mono-2- and di-2-sulfoxides, 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 coadministered drug and dosage) to avoid undesirable drug interactions.

Address correspondence to: Dr. Jacek Wójcikowski, Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343 Kraków, Poland. E-mail: wojcikow{at}if-pan.krakow.pl




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