| Title | Characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine. | | Author(s) | Wójcikowski J, Maurel P, Daniel WA | | Institution | Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343 Kraków, Poland. wojcikow@if-pan.krakow.pl | | Source | Drug Metab Dispos 2006 Mar; 34(3):471-6. | | MeSH | Animals
Antipsychotic Agents
Biotransformation
Catalysis
Cloning, Molecular
Cytochrome P-450 Enzyme System
Humans
In Vitro
Insects
Microsomes, Liver
Piperidines
Research Support, Non-U.S. Gov't
Thioridazine
| | Abstract | 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 alpha1 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. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 16272405 |
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