In animal health risk assessment, hazard characterisation of feed additives has been often using the default uncertainty factor (UF) of 100 to translate a no-observed-adverse-effect level in test species (rat, mouse, dog, rabbit) to a 'safe' level of chronic exposure in farm and companion animal species. Historically, both 10-fold factors have been further divided to include chemical-specific data in both dimensions when available. For cats (Felis Sylvestris catus), an extra default UF of 5 is applied due to the species' deficiency in particularly glucuronidation and glycine conjugation. This paper aims to assess the scientific basis and validity of the UF for inter-species differences in kinetics (4.0) and the extra UF applied for cats through a comparison of kinetic parameters between rats and cats for 30 substrates of phase I and phase II metabolism. When the parent compound undergoes glucuronidation the default factor of 4.0 is exceeded, with exceptions for zidovudine and S-carprofen. Compounds that were mainly renally excreted did not exceed the 4.0-fold default. Mixed results were obtained for chemicals which are metabolised by CYP3A in rats. When chemicals were administered intravenously the 4.0-fold default was not exceeded with the exception of clomipramine, lidocaine and alfentanil. The differences seen after oral administration might be due to differences in first-pass metabolism and bioavailability. Further work is needed to further characterise phase I, phase II enzymes and transporters in cats to support the development of databases and in silico models to support hazard characterisation of chemicals particularly for feed additives.

中文翻译：

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药物在猫（Felix sylvestris catus）体内的代谢和药代动力学及其对饲料添加剂和污染物风险评估的影响

在动物健康风险评估中，饲料添加剂的危害表征通常使用默认的不确定性因子 (UF) 100 将测试物种（大鼠、小鼠、狗、兔）中未观察到的不利影响水平转化为“农场和伴侣动物物种慢性接触的安全”水平。从历史上看，这两个 10 倍因素都被进一步划分为在可用时包括两个维度中的化学特定数据。对于猫 (Felis Sylvestris catus)，由于该物种特别缺乏葡萄糖醛酸化和甘氨酸结合，因此应用额外的默认 UF 5。本文旨在评估 UF 对种间动力学差异的科学基础和有效性 (4. 0) 以及通过比较大鼠和猫之间 30 种 I 期和 II 期代谢底物的动力学参数，将额外的超滤应用于猫。当母体化合物进行葡萄糖醛酸化时，默认因子 4.0 被超过，但齐多夫定和 S-卡洛芬除外。主要通过肾脏排泄的化合物不超过默认值的 4.0 倍。对于在大鼠中被 CYP3A 代谢的化学物质，获得了不同的结果。除了氯米帕明、利多卡因和阿芬太尼外，当静脉注射化学品时，没有超过 4.0 倍的默认值。口服给药后出现的差异可能是由于首过代谢和生物利用度的差异。需要进一步的工作来进一步表征第一阶段，