Authors: Tiina Karonen Jouko Laitila Mikko Niemi Pertti J Neuvonen Janne T Backman
Publish Date: 2011/11/23
Volume: 68, Issue: 5, Pages: 681-688
Abstract
Zafirlukast is a substrate of cytochrome P450 2C9 CYP2C9 and cytochrome P450 3A4 CYP3A4 in vitro but the role of these enzymes in its metabolism in vivo is unknown To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism we studied the effects of fluconazole and itraconazole on its pharmacokinetics PKIn a randomized crossover study 12 healthy volunteers ingested fluconazole 200 mg first dose 400 mg once daily itraconazole 100 mg first dose 200 mg twice daily or placebo twice daily for 5 days and on day 3 20 mg zafirlukast Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 hFluconazole increased the total area under the plasma concentrationtime curve AUC of zafirlukast 16fold 95 confidence interval CI 13–20fold P 0001 and its peak plasma concentration 15fold 95 CI 12–20fold P 005 Fluconazole did not affect the time of peak plasma concentration or elimination halflife of zafirlukast None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase eg the ratio to control of the total AUC of zafirlukast was 10 95 CI 082–12 during the itraconazole phaseWe thank Mrs Eija MäkinenPulli and Mrs Lisbet Partanen for skilful technical assistance This study was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation Finland None of the authors has any financial or personal relationships that could be perceived as influencing the research described The experiments comply with the current laws of Finland and the study protocol was approved by the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District and by the Finnish Medicines Agency
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