Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model
Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model
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DOI：
10.1093/toxsci/53.2.185
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发表时间：
2000-02-01
影响因子：
3.8
通讯作者：
Conolly, RB
中科院分区：
文献类型：
--
作者：
Fisher, JW;Dorman, DC;Conolly, RB
为猴开发了基于生理学的药代动力学（PBPK）模型，以解释吸入甲醇蒸气在肺中的全身吸收分数。使用未报告的D. C. Dorman等人，（1994，Toxicol Appl Pharmacol，128，229-238）仅肺部暴露研究。呼出的[C-14]-甲醇的累积量与暴露持续时间（0.5至2小时）和浓度（10至900 ppm）呈线性关系。该模型估计，在雌性食蟹猴暴露于10-900 ppm [C-14]甲醇2小时后，40%至81%的吸入[C-14]-甲醇进入肺体循环。全身吸收的吸入[C-14]-甲醇百分比与[C-14]-甲醇暴露浓度之间无明显趋势。使用单一可饱和Michaelis-Menten方程进行模型模拟，其中Vmaxc（代谢能力）设定为15.54 mg/kg/h，Km（亲和常数）设定为0.66 mg/l。[C-14]-甲醇暴露组间的[C-14]-甲醇血液浓度不同，PBPK模型倾向于过度预测[C-14]-甲醇的全身清除率，说明吸入极性溶剂的部分摄取是吸入极性溶剂风险评估的重要考虑因素。
A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [C-14]-methanol was estimated using unreported exhaled breath time course measurements of [C-14]-methanol from the D. C. Dorman et al, (1994, Toxicol Appl Pharmacol, 128, 229-238) lung-only exposure study. The cumulative amount of [C-14]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [C-14]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [C-14]methanol. There was no apparent trend between the percent of inhaled [C-14]-methanol absorbed systemically and the [C-14]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [C-14]-methanol blood concentrations were variable across [C-14]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [C-14]- methanol, Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.