Assessing Kinetic Determinants for Metabolism and Oral Uptake of Octamethylcyclotetrasiloxane (D₄) from Inhalation Chamber Studies

Abstract

The pharmacokinetics of octamethylcyclotetrasiloxane (D₄), a highly lipophilic and well-metabolized volatile cyclic siloxane, are more complex than those of other volatile hydrocarbons. The purpose of the present study was to evaluate rate constants for saturable metabolism in the body, to estimate possible presystemic D₄ clearance by respiratory-tract tissues, and to assess rate constants for uptake of D₄ after oral dosing. These experiments provided the opportunity to refine current physiologically based pharmacokinetic (PBPK) models for D₄ and to independently estimate key model parameters by sensitive inhalation methods. The PBPK model could only be fitted to gas uptake results when metabolic capacity was included in the respiratory-tract epithelium. The model simulations were highly sensitive to the parameter for total percent of whole-body metabolism allocated to the respiratory tract, with optimal fits observed with this value equal to 5%. Oral uptake of D₄ was evaluated using both closed and open chamber concentration time-course studies after intubation of D₄ in corn oil. Conclusions from the oral uptake studies were also verified by comparison with independent data sets for blood concentrations of D₄ after oral dosing. The pharmacokinetic (PK) analysis of uptake from the gut and release from blood into chamber air results for oral doses from 10 to 300 mg D₄/kg body weight were consistent with a combination of prolonged and slow uptake of D₄ from the gastrointestinal tract and of reduced absorption at higher doses, as well as the extrahepatic clearance of D₄ in pulmonary tissues. These closed chamber gas uptake studies provide a valuable confirmation of the conclusions reached in other pharmacokinetic studies and have uncovered a situation where closed chamber loss is highly sensitive to respiratory-tract clearance. This sensitivity largely arises from the unusual characteristics of D₄: high-affinity metabolic clearance and low blood:air partitioning.