title: 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.
abstract: 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.
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Kensuke P
authors.initials: KP
authors.lastname: Watanabe
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Kawata
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.|Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikenaka
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Shouta M M
authors.initials: SM
authors.lastname: Nakayama
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ishii
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.|Food Control Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
authors.forename: Wageh Sobhi
authors.initials: WS
authors.lastname: Darwish
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.|Department of Pharmacology, Faculty of Veterinary Medicine, Kasetsart University, Lat Yao Chatuchak, Bangkok, Thailand.
authors.forename: Aksorn
authors.initials: A
authors.lastname: Saengtienchai
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Mizukawa
authors.affiliation: Laboratory of Toxicology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay / Q000379:methods*; D001717:Birds / Q000378:metabolism*; D002645:Chickens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004351:Drug Resistance; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007700:Kinetics; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology*; D055442:Metabolome; D008862:Microsomes, Liver / Q000378:metabolism; D017208:Rats, Wistar; D014859:Warfarin / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: C059853:4'-hydroxywarfarin; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System
keywords: Avian; Cytochrome P450; Pharmacokinetics; Species difference; Warfarin