The in vivo metabolism and pharmacokinetics of flunixin meglumine and phenylbutazone have been extensively characterized; however, there are no published reports describing the in vitro metabolism, specifically the enzymes responsible for the biotransformation of these compounds in horses. Due to their widespread use and, therefore, increased potential for drug–drug interactions and widespread differences in drug disposition, this study aims to build on the limited current knowledge regarding P450‐mediated metabolism in horses. Drugs were incubated with equine liver microsomes and a panel of recombinant equine P450s. Incubation of phenylbutazone in microsomes generated oxyphenbutazone and gamma‐hydroxy phenylbutazone. Microsomal incubations with flunixin meglumine generated 5‐OH flunixin, with a kinetic profile suggestive of substrate inhibition. In recombinant P450 assays, equine CYP3A97 was the only enzyme capable of generating oxyphenbutazone while several members of the equine CYP3A family and CYP1A1 were capable of catalyzing the biotransformation of flunixin to 5‐OH flunixin. Flunixin meglumine metabolism by CYP1A1 and CYP3A93 showed a profile characteristic of biphasic kinetics, suggesting two substrate binding sites. The current study identifies specific enzymes responsible for the metabolism of two NSAIDs in horses and provides the basis for future study of drug–drug interactions and identification of reasons for varying pharmacokinetics between horses.

中文翻译：

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马体内负责非甾体抗炎药氟尼辛葡甲胺和保泰松代谢的酶的鉴定和表征。

氟尼辛葡甲胺和保泰松的体内代谢和药代动力学已得到广泛表征；然而，没有公开的报告描述体外代谢，特别是负责这些化合物在马体内生物转化的酶。由于它们的广泛使用，因此增加了药物 - 药物相互作用的可能性和药物处置的广泛差异，本研究旨在建立在关于 P450 介导的马代谢的当前有限知识的基础上。将药物与马肝微粒体和一组重组马 P450 一起孵育。保泰松在微粒体中的孵化产生了保泰松和 γ-羟基保泰松。微粒体与氟尼辛葡甲胺一起孵育产生 5-OH 氟尼辛，其动力学特征表明底物抑制。在重组 P450 检测中，马 CYP3A97 是唯一能够产生保泰松的酶，而马 CYP3A 家族的几个成员和 CYP1A1 能够催化氟尼辛生物转化为 5-OH 氟尼辛。CYP1A1 和 CYP3A93 的氟尼辛葡甲胺代谢显示出双相动力学特征，表明存在两个底物结合位点。目前的研究确定了负责马体内两种 NSAID 代谢的特定酶，并为未来研究药物-药物相互作用和确定马之间不同药代动力学的原因提供了基础。马 CYP3A97 是唯一能够产生保泰松的酶，而马 CYP3A 家族的几个成员和 CYP1A1 能够催化氟尼辛生物转化为 5-OH 氟尼辛。CYP1A1 和 CYP3A93 的氟尼辛葡甲胺代谢显示出双相动力学特征，表明存在两个底物结合位点。目前的研究确定了负责马体内两种 NSAID 代谢的特定酶，并为未来研究药物-药物相互作用和确定马之间不同药代动力学的原因提供了基础。马 CYP3A97 是唯一能够产生保泰松的酶，而马 CYP3A 家族的几个成员和 CYP1A1 能够催化氟尼辛生物转化为 5-OH 氟尼辛。CYP1A1 和 CYP3A93 的氟尼辛葡甲胺代谢显示出双相动力学特征，表明存在两个底物结合位点。目前的研究确定了负责马体内两种 NSAID 代谢的特定酶，并为未来研究药物-药物相互作用和确定马之间不同药代动力学的原因提供了基础。