title: Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in humans during rest and exercise.
abstract: In a recent pharmacokinetic study, six human volunteers were exposed by inhalation to 10 ppm (14)C-D(4) for 1 h during alternating periods of rest and exercise. Octamethylcyclotetrasiloxane (D(4)) 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 D(4) in humans. Consistent with PBPK modeling efforts for D(4) in the rat, a conventional inhalation PBPK model assuming flow-limited tissue uptake failed to adequately describe these data. A refined model with sequestered D(4) in blood, diffusion-limited tissue uptake, and an explicit pathway for D(4) 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 D(4) 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 D(4) (high lipophilicity coupled with high hepatic and exhalation clearance) lead to rapid decreases in free D(4) in blood. The success of D(4) 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 D(4) and metabolites during inhalation exposures.
authors.affiliation: Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Colorado State University, Fort Collins, Colorado 80523, USA. mreddy@colostate.edu
authors.forename: Micaela B
authors.initials: MB
authors.lastname: Reddy
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morrow
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Dobrev
authors.forename: Sudarsanan
authors.initials: S
authors.lastname: Varaprath
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: Plotzke
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Utell
mesh_terms: D000276:Adjuvants, Immunologic / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000280:Administration, Inhalation; D000465:Algorithms; D000818:Animals; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D015444:Exercise / Q000502:physiology*; D005223:Fats / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D015203:Reproducibility of Results; D012146:Rest / Q000502:physiology*; D012833:Siloxanes / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000276:Adjuvants, Immunologic; D002250:Carbon Radioisotopes; D005223:Fats; D012833:Siloxanes; C024064:octamethylcyclotetrasiloxane