A1 Refereed original research article in a scientific journal
Gemfibrozil Impairs lmatinib Absorption and Inhibits the CYP2C8-Mediated Formation of Its Main Metabolite
Authors: Filppula AM, Tornio A, Niemi M, Neuvonen PJ, Backman JT
Publisher: NATURE PUBLISHING GROUP
Publication year: 2013
Journal: Clinical Pharmacology and Therapeutics
Journal name in source: CLINICAL PHARMACOLOGY & THERAPEUTICS
Journal acronym: CLIN PHARMACOL THER
Volume: 94
Issue: 3
First page : 383
Last page: 393
Number of pages: 11
ISSN: 0009-9236
DOI: https://doi.org/10.1038/clpt.2013.92
Abstract
Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (C-max) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the C-max and area under the plasma concentration-time curve (AUC(0-infinity)) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC(0-infinity) of imatinib was unaffected. Furthermore, gemfibrozil reduced the C-max/plasma concentration at 24 h (C-24h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.
Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (C-max) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the C-max and area under the plasma concentration-time curve (AUC(0-infinity)) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC(0-infinity) of imatinib was unaffected. Furthermore, gemfibrozil reduced the C-max/plasma concentration at 24 h (C-24h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.
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