Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in humans during rest and exercise.
Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in humans during rest and exercise.
复制标题
人体休息和运动期间八甲基环四硅氧烷吸入动力学的生理模型。
DOI：
10.1093/toxsci/kfg001
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Utell,MarkJ
中科院分区：
文献类型：
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作者：
Reddy,MicaelaB;Andersen,MelvinE;Morrow,PaulE;Dobrev,IvanD;Varaprath,Sudarsanan;Plotzke,KathleenP;Utell,MarkJ
在最近的一项药代动力学研究中，六名人类志愿者在休息和运动交替期间吸入 10 ppm14C-D4 1 小时。测定呼出气和血液中的八甲基环四硅氧烷 (D4) 浓度。估计血液中的总代谢物浓度，同时测量尿液中的单个代谢物的量。在这里，我们使用这些数据开发人类 D4 的生理学药代动力学 (PBPK) 模型。与大鼠 D4 的 PBPK 建模工作一致，假设流量限制组织摄取的传统吸入 PBPK 模型未能充分描述这些数据。一个精致的模型成功地描述了所有数据，该模型具有血液中隔离的 D4、扩散限制的组织摄取以及 D4 代谢为短链线性硅氧烷的明确途径。根据模型参数计算，这些志愿者的肝提取率为 0.65 至 0.8，即肝脏清除率几乎受到流量限制。人类在运动期间吸入的 D4 保留量减少的原因是运动期间通气/灌注特性的改变以及快速接近稳态条件。代谢物的尿时程排泄与代谢方案一致，其中线性硅氧烷依次水解，然后氧化去甲基化和开环。 D4 的不寻常特性（高亲脂性加上高肝脏和呼气清除率）导致血液中游离 D4 迅速减少。 D4PBPK 模型在人类和大鼠中具有相似的生理结构，其成功增加了人们对该模型用于预测吸入暴露期间 D4 和代谢物的人体组织浓度的实用性的信心。
In a recent pharmacokinetic study, six human volunteers were exposed by inhalation to 10 ppm14C-D4for 1 h during alternating periods of rest and exercise. Octamethylcyclotetrasiloxane (D4) concentrations were determined in exhaled breath and blood. Total metabolite concentrations were estimated in blood, while the amounts of individual metabolites were measured in urine. Here, we use these data to develop a physiologically based pharmacokinetic (PBPK) model for D4in humans. Consistent with PBPK modeling efforts for D4in the rat, a conventional inhalation PBPK model assuming flow-limited tissue uptake failed to adequately describe these data. A refined model with sequestered D4in blood, diffusion-limited tissue uptake, and an explicit pathway for D4metabolism to short-chain linear siloxanes successfully described all data. Hepatic extraction in these volunteers, calculated from model parameters, was 0.65 to 0.8, i.e., hepatic clearance was nearly flow-limited. The decreased retention of inhaled D4seen in humans during periods of exercise was explained by altered ventilation/perfusion characteristics during exercise and a rapid approach to steady-state conditions. The urinary time course excretion of metabolites was consistent with a metabolic scheme in which sequential hydrolysis of linear siloxanes followed oxidative demethylation and ring opening. The unusual properties of D4(high lipophilicity coupled with high hepatic and exhalation clearance) lead to rapid decreases in free D4in blood. The success of D4PBPK models with a similar physiological structure in both humans and rats increases confidence in the utility of the model for predicting human tissue concentrations of D4and metabolites during inhalation exposures.