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

Autor:	Andreas Austgulen Westin, S. Taylor, Simon J. C. Davies, Ingrid Castberg, Glyn Lewis, Martin S. Lennard, Olav Spigset
Rok vydání:	2010
Předmět:	medicine.medical_specialty Perphenazine CYP2D6 medicine.diagnostic_test business.industry Carbamazepine Zuclopenthixol Levomepromazine Psychiatry and Mental health chemistry.chemical_compound Endocrinology chemistry Pharmacokinetics Therapeutic drug monitoring Internal medicine medicine Ketoconazole business medicine.drug
Zdroj:	Acta Psychiatrica Scandinavica. 122:444-453
ISSN:	0001-690X
DOI:	10.1111/j.1600-0447.2010.01619.x
Popis:	Davies SJC, Westin AA, Castberg I, Lewis G, Lennard MS, Taylor S, Spigset O. Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies. 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.
Databáze:	OpenAIRE
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