John Wiley & Sons, Ltd.

CYP‐mediated warfarin metabolic ability is not a critical determinant of warfarin sensitivity in avian species; in vitro assays in several birds and in vivo assays in chicken

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Coumarin derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin (WF) a classic coumarin derivative, chicken have a high LD50 while mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to WF are to be expected. We previously reported substantial differences in WF metabolism among avian species, however the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, we sought to provide an in‐depth characterization of WF metabolism in birds using in vivo and in vitro approaches. We performed a kinetic analysis of WF metabolism using liver microsomes of four avian species and found that the metabolic ability of the chicken and crow are much higher in comparison to the mallard and ostrich. Analysis of in vivo metabolites from chicken showed that excretions predominantly consisted of 4'‐hydroxywarfarin, which was consistent with the in vitro results. Pharmacokinetic analysis suggested that chickens have an unexpectedly long half‐life despite showing high metabolic ability in vitro. These results suggest that the half‐life of WF in other bird species could be longer than in chicken, and that WF metabolism may not be a critical determinant of species difference with respect to WF sensitivity. This article is protected by copyright. All rights reserved

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