Exponent Inc, Alexandria, VA, 22314, USA.
Exponent Inc, Washington DC, 20036, USA.
Regul Toxicol Pharmacol. 2021 Aug;124:104962. doi: 10.1016/j.yrtph.2021.104962. Epub 2021 May 19.
Afidopyropen is an insecticide that acts as a transient receptor potential vanilloid subtype (TRPV) channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including chronic toxicity and carcinogenicity in rats and mice. The current study evaluates the toxicokinetic properties of afidopyropen and its plasma metabolites in rats at dose levels where the pharmacokinetics (PK) are linear and nonlinear in an attempt to identify a point of inflection. Based on the results of this study and depending on the analysis method used, the kinetically derived maximum dose (KMD) is estimated to be between 2.5 and 12.5 mg/kg bw/d with linearity observed at doses below 2.5 mg/kg bw/d. A defined point of inflection could not be determined. These data demonstrate that consideration of PK is critical for improving the dose-selection in toxicity studies as well as to enhance human relevance of the interpretation of animal toxicity studies. The study also demonstrates the technical difficulty in obtaining a defined point of inflection from in vivo PK data.
阿维菌素是一种杀虫剂，在靶标昆虫的琴状感器中作为瞬时受体电位香草酸亚型（TRPV）通道调节剂发挥作用，已针对包括慢性毒性和致癌性在内的广泛毒性终点在大鼠和小鼠中进行了评估。本研究评估了阿维菌素及其在大鼠中的血浆代谢物的毒代动力学特性，在这些剂量水平下，药代动力学（PK）在尝试确定拐点时呈线性和非线性。基于这项研究的结果，并根据所使用的分析方法，动力学衍生的最大剂量（KMD）估计在 2.5 至 12.5mg/kg bw/d 之间，在低于 2.5mg/kg bw/d 的剂量下观察到线性。无法确定明确的拐点。这些数据表明，在毒性研究中考虑 PK 对于改善剂量选择以及提高动物毒性研究的人类相关性至关重要。该研究还表明，从体内 PK 数据中获得明确拐点存在技术困难。
