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
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
复制标题
细胞色素 P450 介导的华法林代谢能力并不是鸟类华法林敏感性的关键决定因素：几种鸟类的体外测定和鸡的体内测定
DOI：
10.1002/etc.3062
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发表时间：
2015
影响因子：
4.1
通讯作者：
Ishizuka M
中科院分区：
文献类型：
--
作者：
Watanabe KP;Kawata M;Ikenaka Y;Nakayama SMM;Ishii C;Darwish WS;Saengtienchai A;Mizukawa H;Ishizuka M
用于啮齿动物控制的香豆素衍生物抗凝血灭鼠剂对野生鸟类种群构成严重风险。对于华法林（一种经典的香豆素衍生物），鸡的半数致死量（LD 50）较高，而哺乳动物的LD 50通常较低。预期对华法林的敏感性存在较大的种属间差异。作者先前报告了禽类之间华法林代谢的显著差异;然而，即使在鸡中，实际的体内药代动力学也尚未阐明。在本研究中，作者试图使用体内和体外方法深入表征鸟类的华法林代谢。利用4种鸟类肝微粒体对华法令代谢进行了动力学分析，发现鸡和乌鸦的代谢能力远高于野鸭和鸵鸟。鸡体内代谢物分析表明，排泄物主要由4′-羟基华法林组成，这与体外结果一致。药代动力学分析表明，尽管鸡在体外显示出高代谢能力，但其半衰期出乎意料地长。结果表明，华法林在其他鸟类中的半衰期可能长于鸡，华法林代谢可能不是华法林敏感性方面物种差异的关键决定因素。Environ Toxicol Chem 2015;34：2328-2334。© 2015 SETAC
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 Chem2015;34:2328–2334. © 2015 SETAC