Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan.
Regul Toxicol Pharmacol. 2010 Nov;58(2):252-8. doi: 10.1016/j.yrtph.2010.06.008. Epub 2010 Jun 23.
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.
本研究基于使用相关肝微粒体测定的体外代谢参数、通过计算机推导的系数、从文献中得出的生理参数以及先前在大鼠中开发的基于生理学的药代动力学模型，为人类丙烯腈定义了简化的基于生理学的药代动力学（PBPK）模型。该模型主要由丙烯腈的化学吸收隔室、代谢隔室和中央隔室组成。通过与大鼠口服丙烯腈（30mg/kg，无观察到不良反应水平）14 天后从体内获得的血液和尿液的实验药代动力学值进行比较，对先前的大鼠模型进行了评估。使用来自大鼠肝微粒体和混合人肝微粒体的数据建立了丙烯腈的体外消除率。根据计算，丙烯腈在体内会被迅速吸收和清除，这与大鼠在重复低剂量处理后的实验结果一致。这些结果表明，简化的丙烯腈 PBPK 模型可用于人体的正向剂量测定方法。该模型也可用于模拟因接触低剂量化学品而导致的其他相关化合物的血液浓度。
