Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies
- PMID:20946203
- DOI: 10.1111/j.1600-0447.2010.01619.x
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.
© 2010 John Wiley & Sons A/S.
Comment in
- How to dose a psychotropic drug: beyond therapeutic drug monitoring to genotyping the patient.Stahl SM.Stahl SM.Acta Psychiatr Scand. 2010 Dec;122(6):440-1. doi: 10.1111/j.1600-0447.2010.01606.x. Epub 2010 Sep 29.Acta Psychiatr Scand. 2010.PMID:20880158No abstract available.
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