title: Gemfibrozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation of its main metabolite.
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 (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0-∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 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.
authors: Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
authors: A M
authors: AM
authors: Filppula
authors: A
authors: A
authors: Tornio
authors: M
authors: M
authors: Niemi
authors: P J
authors: PJ
authors: Neuvonen
authors: J T
authors: JT
authors: Backman
mesh_terms: D000042:Absorption; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D004336:Drug Antagonism; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000960:Hypolipidemic Agents; D010879:Piperazines; D011743:Pyrimidines; C584971:N-desmethylimatinib; D000068877:Imatinib Mesylate; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil