Physiological Modeling of Inhalation Kinetics of Octamethylcyclotetrasiloxane in Humans during Rest and Exercise

• Published in: Toxicological sciences 2003-03, Vol.72 (1), p.3-18
• Main Authors: Reddy, Micaela B., Andersen, Melvin E., Morrow, Paul E., Dobrev, Ivan D., Varaprath, Sudarsanan, Plotzke, Kathleen P., Utell, Mark J.
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - blood; Adjuvants, Immunologic - pharmacokinetics; Adjuvants, Immunologic - urine; Administration, Inhalation; Algorithms; Animals; Biological and medical sciences; Carbon Radioisotopes; Chemical and industrial products toxicology. Toxic occupational diseases; Dose-Response Relationship, Drug; Exercise - physiology; Fats - metabolism; flow-limited metabolism; Humans; inhalation pharmacokinetics; lipid sequestration; Liver - metabolism; Male; Medical sciences; Models, Biological; octamethylcylcotetrasiloxane; PBPK modeling; Rats; Reproducibility of Results; Rest - physiology; Siloxanes - metabolism; Siloxanes - pharmacokinetics; Toxicology; vapor retention; Various organic compounds
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfg001

In a recent pharmacokinetic study, six human volunteers were exposed by inhalation to 10 ppm 14C-D4 for 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 D4 in humans. Consistent with PBPK modeling efforts for D4 in the rat, a conventional inhalation PBPK model assuming flow-limited tissue uptake failed to adequately describe these data. A refined model with sequestered D4 in blood, diffusion-limited tissue uptake, and an explicit pathway for D4 metabolism 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 D4 seen 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 D4 in blood. The success of D4 PBPK 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 D4 and metabolites during inhalation exposures.