Unbound MEDLINE

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

Abstract

OBJECTIVE
Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes.
METHOD
In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine.
RESULTS
In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance.
CONCLUSION
The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

Links

  • Publisher Full Text

    • Authors

    Davies SJ, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O

    Institution

    University of Bristol, UK. simon.davies@bristol.ac.uk

    Source

    Acta psychiatrica Scandinavica 122:6 2010 Dec pg 444-53

    MeSH

    Adult
    Antidepressive Agents, Second-Generation
    Antifungal Agents
    Antimalarials
    Antimanic Agents
    Antipsychotic Agents
    Carbamazepine
    Clopenthixol
    Cytochrome P-450 Enzyme System
    Dose-Response Relationship, Drug
    Drug Interactions
    Drug Monitoring
    Female
    Fluoxetine
    Humans
    Ketoconazole
    Male
    Methotrimeprazine
    Microsomes, Liver
    Middle Aged
    Paroxetine
    Quinidine

    Pub Type(s)

    In Vitro
    Journal Article

    Language

    eng

    PubMed ID

    20946203