药代动力学
基于生理学的药代动力学模型
体内分布
药理学
脂质体
两性霉素B
药品
化学
分布(数学)
单核吞噬细胞系统
体内
医学
药物输送
分配量
药物相互作用
生物利用度
最大值
药效学
毒品携带者
曲线下面积
抗真菌
病理
体外
生物化学
皮肤病科
作者
Leonid Kagan,Pavel Gershkovich,Kishor M. Wasan,Donald E. Mager
标识
DOI:10.1007/s11095-013-1127-z
摘要
To investigate the biodistribution of amphotericin B (AmB) in mice and rats following administration of liposomal AmB (AmBisome®) using a physiologically-based pharmacokinetic (PBPK) modeling framework and to utilize this approach for predicting AmBisome® pharmacokinetics in human tissues.AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of nonliposomal and liposomal AmB to mice and rats, were extracted from literature. The whole-body PBPK model was constructed and incorporated nonliposomal and liposomal subcompartments. Various structural models for individual organs were evaluated. Allometric relationships were incorporated into the model to scale parameters based on species body weight.A non-Michaelis-Menten mechanism was included into the structure of the liver and spleen liposomal compartments to describe saturable uptake of particles by the reticuloendothelial system. The model successfully described plasma and tissue pharmacokinetics of AmB after administration of AmBisome® to rats and mice.The dual PBPK model demonstrated good predictive performance by reasonably simulating AmB exposure in human tissues. This modeling framework can be potentially utilized for optimizing AmBisome® therapy in humans and for investigating pathophysiological factors controlling AmB pharmacokinetics and pharmacodynamics.
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