Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin.
Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).
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Département Universitaire de Psychiatrie Adulte, Prilly-Lausanne, Switzerland.
Guentert
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TW
Schãublin-Loidl
M
M
Stabl
M
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Koeb
L
L
Powell
K
K
Baumann
P
P
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000378:metabolism*; D000928:Antidepressive Agents / Q000097:blood; D014150:Antipsychotic Agents / Q000097:blood*; D000996:Antitussive Agents / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003866:Depressive Disorder / Q000097:blood*; D003915:Dextromethorphan / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008653:Mesoridazine / Q000097:blood; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010640:Phenothiazines / Q000097:blood; D013237:Stereoisomerism; D013881:Thioridazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood*
D000927:Anticonvulsants; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000996:Antitussive Agents; D010640:Phenothiazines; D008653:Mesoridazine; D003915:Dextromethorphan; C041140:thioridazine-5-sulfoxide; D003577:Cytochrome P-450 Enzyme System; C040634:sulforidazine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013881:Thioridazine; D008617:Mephenytoin