Lee K M, Dill J A, Chou B J, Roycroft J H
Preclinical Drug Development-Northwest Operations, Battelle, Richland, Washington, USA.
Toxicol Appl Pharmacol. 1998 Dec;153(2):211-26. doi: 10.1006/taap.1998.8518.
2-Butoxyethanol (2BE) is used extensively in the production of cleaning agents and as a general solvent. It is primarily metabolized in the liver to 2-butoxyacetic acid (2BAA), which is excreted in urine. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model describing the toxicokinetic behavior of 2BE and 2BAA in different species following repeated, long-term exposures. The PBPK model was first developed for short-term 2BE exposure to male rats. Allometric scaling was employed to estimate physiological and biochemical model parameters based on body weight. To accommodate differences in 2BE toxicokinetics in female rats, a higher Vmax for 2BE metabolism to 2BAA, higher plasma protein binding sites for 2BAA, and lower Vmax for 2BAA excretion through the kidney were incorporated into the model. For mice, a higher Vmax for 2BE metabolism to 2BAA for both sexes and higher plasma protein binding sites for 2BAA for female mice were also incorporated into the model. Subsequently, the model was expanded to simulate 2BE and 2BAA toxicokinetics for long-term, repeated exposures by incorporating time-dependent changes in model parameters. To reflect physiological/biochemical changes in animals during a chronic exposure, parameters for cardiac output, body composition, metabolic capacity, protein binding, or capacity of renal excretion were adjusted over time depending on species and sex. Sensitivity analysis was performed to better understand how sensitive model responses were to uncertainties in input parameters. The resulting PBPK model was used to simulate toxicokinetic data acquired during a 2-year inhalation toxicity and carcinogenicity study in male and female F344/N rats and B6C3F1 mice.
2-丁氧基乙醇（2BE）广泛用于清洁剂生产及作为通用溶剂。它主要在肝脏中代谢为2-丁氧基乙酸（2BAA），并通过尿液排出。本研究的目的是建立一个基于生理的药代动力学（PBPK）模型，描述重复长期暴露后不同物种中2BE和2BAA的毒代动力学行为。该PBPK模型首先针对雄性大鼠短期暴露于2BE进行开发。采用异速缩放法根据体重估计生理和生化模型参数。为适应雌性大鼠2BE毒代动力学的差异，模型中纳入了2BE代谢为2BAA的更高Vmax、2BAA更高的血浆蛋白结合位点以及2BAA经肾脏排泄的更低Vmax。对于小鼠，模型中还纳入了两性2BE代谢为2BAA的更高Vmax以及雌性小鼠2BAA更高的血浆蛋白结合位点。随后，通过纳入模型参数随时间的变化，将模型扩展以模拟长期重复暴露的2BE和2BAA毒代动力学。为反映慢性暴露期间动物的生理/生化变化，根据物种和性别，随时间调整心输出量、身体组成、代谢能力、蛋白结合或肾脏排泄能力等参数。进行敏感性分析以更好地了解模型响应对输入参数不确定性的敏感程度。所得的PBPK模型用于模拟在雄性和雌性F344/N大鼠及B6C3F1小鼠的两年吸入毒性和致癌性研究中获取的毒代动力学数据。
