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Gemfibrozil Impairs Imatinib Absorption and Inhibits the CYP2C8‐Mediated Formation of Its Main Metabolite
Author(s) -
Filppula A M,
Tornio A,
Niemi M,
Neuvonen P J,
Backman J T
Publication year - 2013
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2013.92
Subject(s) - cmax , gemfibrozil , imatinib , pharmacology , cyp2c8 , pharmacokinetics , chemistry , crossover study , metabolite , cyp3a4 , oral administration , drug interaction , placebo , medicine , cytochrome p450 , metabolism , cholesterol , alternative medicine , myeloid leukemia , pathology
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–∞ ) of N ‐desmethylimatinib by 56 and 48% ( P < 0.001), respectively, whereas the AUC 0–∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the C max /plasma concentration at 24 h ( C 24 h ) 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. Clinical Pharmacology & Therapeutics (2013); 94 3, 383–393. doi: 10.1038/clpt.2013.92