IngentaConnect Effects of cytochrome P450 3A modulators ketoconazole and carbama...

Abstract:

Aims

To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments. Methods

The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks. Results

CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma C_max by 3.35-fold, from 45 to 150 ng ml⁻¹ (mean C_max ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h⁻¹ (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma C_max by 80%, from 1042 to 205 ng ml⁻¹ (mean C_max ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h⁻¹ (mean ratio 90% CI 6.04, 9.28). Conclusions

Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine.

Keywords: carbamazepine; drug interaction; ketoconazole; pharmacokinetics; quetiapine

Document Type: Research article

DOI: 10.1111/j.1365-2125.2005.02507.x

Affiliations: 1: Department of Psychiatry, Cincinnati Veterans Affairs Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 2: AstraZeneca Pharmaceuticals LP, Wilmington, DE 3: AstraZeneca Pharmaceuticals LP, Boston, MA, USA

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Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics