The effect of fenofibric acid on the pharmacokinetics and pharmacodynamics of warfarin in rats |
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Authors: | Chaorui Guo Siqi Xue Xiufen Zheng Yang Lu Di Zhao |
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Institution: | Clinical Pharmacokinetics Research Laboratory, China Pharmaceutical University, Nanjing, China and |
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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 Cmax and prolonged t1/2 of 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 (Ki value 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. |
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Keywords: | CYP450 drug interactions fenofibric acid protein binding warfarin |
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