open access

https://hdl.handle.net/2115/62929

Cytochrome P450-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

英語

Pharmacokinetics

2015-10

Wiley-Blackwell

Environmental Toxicology and Chemistry

34(10)

2328-2334

Coumarin-derivative anticoagulant rodenticides used for rodent control are posing a serious risk to wild bird populations. For warfarin, a classic coumarin derivative, chickens have a high median lethal dose (LD50), whereas mammalian species generally have much lower LD50. Large interspecies differences in sensitivity to warfarin are to be expected. The authors previously reported substantial differences in warfarin metabolism among avian species; however, the actual in vivo pharmacokinetics have yet to be elucidated, even in the chicken. In the present study, the authors sought to provide an in-depth characterization of warfarin metabolism in birds using in vivo and in vitro approaches. A kinetic analysis of warfarin metabolism was performed using liver microsomes of 4 avian species, and the metabolic abilities of the chicken and crow were much higher in comparison with those of the mallard and ostrich. Analysis of in vivo metabolites from chickens 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. The results suggest that the half-life of warfarin in other bird species could be longer than that in the chicken and that warfarin metabolism may not be a critical determinant of species differences with respect to warfarin sensitivity. Environ Toxicol Chem 2015;34:2328-2334. (c) 2015 SETAC

学術雑誌論文

Accepted Manuscript

This is the peer reviewed version of the following article: Watanabe KP, Kawata M, Ikenaka Y, Nakayama SMM, Ishii C, Darwish WS, Saengtienchai A, Mizukawa H, Ishizuka M. 2015. Cytochrome P450-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. Environ Toxicol Chem 34:2328-2334, which has been published in final form at http://dx.doi.org/10.1002/etc.3062. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

0730-7268

1552-8618

AA10627935