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Xenobiotica
the fate of foreign compounds in biological systems
Volume 48, 2018 - Issue 4
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Animal Pharmacokinetics and Metabolism

The effect of fenofibric acid on the pharmacokinetics and pharmacodynamics of warfarin in rats

, , , , , & show all
Pages 400-406 | Received 21 Jan 2017, Accepted 11 Mar 2017, Published online: 31 Mar 2017
 

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.

Acknowledgements

This study was supported by National Natural Science Foundation of China (Nos. 81473272, 81503148).

Declaration of interest

No declaration of interest needs to be reported.

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