title: The effect of fenofibric acid on the pharmacokinetics and pharmacodynamics of warfarin in rats.
abstract: 1. Case reports have shown that coadministration of fenofibric acid (FA) could increase bleeding risks of warfarin, but the mechanisms remained unknown. We therefore investigated the pharmacokinetic and pharmacodynamic interaction between warfarin and FA in rats. 2. Rats received warfarin alone (2 mg/kg) or coadministered with FA (100 mg/kg). FA significantly increased the exposure to warfarin, and decreased that to 7-hydroxywarfarin in rats nearly by two-fold, meanwhile increased Cmaxand prolonged t1/2of warfarin. Anticoagulant activity significantly increased, with prothrombin time (PT) up to 199 ± 33 s in coadministered group (approximately ten-fold compared with rats received warfarin alone). Incubation experiments illustrated FA inhibited CYP2C6 and CYP3A1/2 with the IC50 values of 6.98 and 16.14 μM, and inhibited the metabolism of warfarin (Kivalue of 2.21 μM). Meanwhile, FA decreased the plasma protein binding of warfarin in vitro. 3. Our data suggested that the altered pharmacokinetics and pharmacodynamics of warfarin in rats was primarily attributed to the inhibition of metabolism. Anticoagulant activity monitoring or warfarin dose lowering needs to be considered when patients are coadministered with FA.
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.
authors.forename: Chaorui
authors.initials: C
authors.lastname: Guo
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.
authors.forename: Siqi
authors.initials: S
authors.lastname: Xue
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
authors.affiliation: a Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University , Nanjing , China and.|b Pharmacy Experiment Education Demonstration Center, China Pharmaceutical University , Nanjing , China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C006012:fenofibric acid; D011345:Fenofibrate
keywords: CYP450; drug interactions; fenofibric acid; protein binding; warfarin