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

基于生理学的药代动力学模型 八甲基环四硅氧烷 药代动力学 化学 药理学 吸入 呼吸道 吸收(声学) 胃肠道 加药 新陈代谢 口服 呼吸系统 麻醉 医学 内科学 生物化学 材料科学 复合材料 高分子化学
作者
Ivan D. Dobrev,Andy Nong,Kai Liao,Micaela B. Reddy,Kathleen P. Plotzke,Melvin E. Andersen
出处
期刊:Inhalation Toxicology [Taylor & Francis]
卷期号:20 (4): 361-373 被引量:13
标识
DOI:10.1080/08958370801903743
摘要

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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
2秒前
小二郎应助房山季鸟猴采纳,获得10
2秒前
3秒前
can完成签到,获得积分10
3秒前
zhongzihao完成签到,获得积分20
4秒前
小蘑菇应助MaYue采纳,获得10
4秒前
4秒前
孙福禄应助机智的然然采纳,获得10
4秒前
GooJohn发布了新的文献求助10
5秒前
NexusExplorer应助杜兰特工队采纳,获得10
6秒前
6秒前
6秒前
7秒前
FashionBoy应助鲤跃采纳,获得10
8秒前
阳光c完成签到 ,获得积分10
8秒前
威武的手链完成签到,获得积分20
9秒前
sxr完成签到,获得积分10
9秒前
zhongzihao发布了新的文献求助10
10秒前
10秒前
在水一方应助闪闪采纳,获得10
10秒前
Jay发布了新的文献求助10
11秒前
灰灰子发布了新的文献求助10
11秒前
量子星尘发布了新的文献求助10
12秒前
12秒前
小丑鱼儿发布了新的文献求助10
14秒前
XYN1发布了新的文献求助10
14秒前
17秒前
17秒前
LiuLiu完成签到,获得积分10
18秒前
樱桃小热巴完成签到 ,获得积分10
18秒前
19秒前
19秒前
不低头完成签到,获得积分10
19秒前
大鱼完成签到,获得积分10
20秒前
20秒前
XYN1完成签到,获得积分10
20秒前
MaYue发布了新的文献求助10
21秒前
21秒前
21秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988868
求助须知:如何正确求助?哪些是违规求助? 3531255
关于积分的说明 11253071
捐赠科研通 3269858
什么是DOI,文献DOI怎么找? 1804822
邀请新用户注册赠送积分活动 881994
科研通“疑难数据库(出版商)”最低求助积分说明 809035