Dobrev Ivan D, Nong Andy, Liao Kai H, Reddy Micaela B, Plotzke Kathleen P, Andersen Melvin E
Center for Environmental Toxicology and Technology, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USA.
Inhal Toxicol. 2008 Feb;20(4):361-73. doi: 10.1080/08958370801903743.
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.
八甲基环四硅氧烷（D4）是一种高度亲脂且代谢良好的挥发性环状硅氧烷，其药代动力学比其他挥发性碳氢化合物更为复杂。本研究的目的是评估体内饱和代谢的速率常数，估计呼吸道组织对D4可能的首过清除率，并评估口服给药后D4的摄取速率常数。这些实验为完善当前基于生理学的D4药代动力学（PBPK）模型以及通过灵敏的吸入方法独立估计关键模型参数提供了机会。只有当呼吸道上皮细胞包含代谢能力时，PBPK模型才能拟合气体摄取结果。模型模拟对分配给呼吸道的全身代谢总百分比参数高度敏感，当该值等于5%时观察到最佳拟合。在玉米油中插管给予D4后，使用密闭和开放腔室浓度-时间进程研究评估了D4的口服摄取。口服摄取研究的结论也通过与口服给药后D4血药浓度的独立数据集进行比较得到了验证。对10至300 mg D4/kg体重口服剂量的肠道摄取和血液向腔室空气中释放的药代动力学（PK）分析结果表明，D4从胃肠道的摄取延长且缓慢，高剂量时吸收减少，以及D4在肺组织中的肝外清除，这些情况相互结合。这些密闭腔室气体摄取研究为其他药代动力学研究得出的结论提供了有价值的证实，并揭示了一种密闭腔室损失对呼吸道清除高度敏感的情况。这种敏感性很大程度上源于D4的特殊特性：高亲和力代谢清除和低血-气分配系数。
