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

@article{Eap1996PlasmaLO,
  title={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},
  author={Chin B. Eap and Theodor W. Guentert and Martina Sch{\"a}ublin‐Loidl and Max Stabl and Liliane Koeb and Kerry Powell and Pierre Baumann},
  journal={Clinical Pharmacology \& Therapeutics},
  year={1996},
  volume={59}
}
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… 
Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients.
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Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype
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Racemization and degradation of thioridazine and thioridazine 2-sulfone in human plasma and aqueous solutions.
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Pharmacokinetic Drug Interaction Potential of Risperidone With Cytochrome P450 Isozymes as Assessed by the Dextromethorphan, the Caffeine, and the Mephenytoin Test
TLDR
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Steady state concentrations of the enantiomers of mianserin and desmethylmianserin in poor and in homozygous and heterozygous extensive metabolizers of debrisoquine.
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Degradation and configurational changes of thioridazine 2-sulfoxide.
TLDR
The results showed that both enantiomers were stable at varying temperatures, pH and ionic strengths; however, solubility problems were observed, mainly at pH 8.5.
Comparison of the Effects of Thioridazine and Mesoridazine on the QT Interval in Healthy Adults After Single Oral Doses
TLDR
Thioridazine and mesoridazine are associated with similar effects on the QTc interval and the area under the effect–time curve over 8 h following drug administration was similar between the two drugs.
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References

SHOWING 1-10 OF 35 REFERENCES
Determination of the enantiomers of thioridazine, thioridazine 2-sulfone, and of the isomeric pairs of thioridazine 2-sulfoxide and thioridazine 5-sulfoxide in human plasma.
TLDR
The results show a high enantioselectivity in the metabolism of this drug: the (R)/(S) ratios for THD, THD 2-SO (FE), THD2-SO2, ThD 5- SO (FE) and THD 5 -SO (SE) were found to be 3.90, 1.22, 6.10, 4.09 and 28.0, respectively.
Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype
TLDR
The formation of mesoridazine from thioridazine and the 4‐hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thIORidazine ring‐sulphoxide is probably formed mainly by another enzyme.
Enantioselective amitriptyline metabolism in patients phenotyped for two cytochrome P450 isozymes
In 26 hospitalized patients with depression, a combined pharmacogenetic test with dextromethorphan, a substrate of cytochrome P450IID6, and mephenytoin, the S‐form of which is hydroxylated by a
Light‐Induced Racemization: Artifacts in the Analysis of the Diastereoisomeric Pairs of Thioridazine 5‐Sulfoxide in the Plasma and Urine of Patients Treated with Thioridazine
TLDR
Because it is known that the ring sulfoxide contributes to the cardiotoxicity of the drug even more potently than the parent compound does, these results justify further studies to determine whether there is stereoselectivity in the cardiotsoxicity of THD 5-SO.
Receptor affinity, neurochemistry and behavioral characteristics of the enantiomers of thioridazine: Evidence for different stereoselectivities at D1 and D2 receptors in rat brain
TLDR
It was concluded that (+)- and (-)-thioridazine act as partially selective D2 and D1 antagonists, respectively, and clinical administration of only one enantiomer of thIORidazine, rather than the currently prescribed racemate, may result in an improved therapeutic profile and so be worthy of further investigation.
Dextromethorphan and Mephenytoin Phenotyping of Patients Treated with Thioridazine or Amitriptyline
TLDR
The dextromethorphan pharmacogenetic test can be used for clinical purposes, but to avoid artefacts it should be done after a washout period, especially after treatment with thioridazine; testing with mephenytoin is less likely to be influenced by thIORidazine or amitriptyline.
Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose.
TLDR
Although all four drugs increased the QRS and Q-Tc interval, ventricular arrhythmias and "torsades de pointes" were seen only in dogs receiving the ring sulfoxide.
Metabolism of piperidine-type phenothiazine antipsychotic agents. IV. Thioridazine in dog, man and rat.
TLDR
Interspecies comparison of the lactam metabolites indicated that both qualitatively and quantitatively, man more closely resembled rat than dog, therefore rat may be a more suitable animal than dog to undertake further study of the importance of C-oxidation of the piperidine ring of this class of drug.
Artifacts in the analysis of thioridazine and other neuroleptics.
TLDR
The results show that light significantly affects the analysis of thioridazine and its metabolites and some compounds may be readily oxidized by peroxide-containing solvents.
The mephenytoin oxidation polymorphism is partially responsible for the N‐demethylation of imipramine
TLDR
In conclusion, this and an earlier study show that the oxidation of imipramine is mediated by means of two different polymorphic P450 isozymes, 2‐hydroxylation by way of the sparteine oxygenase (P450IID6) and demethylation by Way of the mephenytoin oxygen enzyme (P 450IIC8).
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