溶解度
基于生理学的药代动力学模型
药代动力学
化学
药品
溶解
药理学
口服
吸收(声学)
生物利用度
色谱法
医学
材料科学
有机化学
复合材料
作者
Joerg Berghausen,Frank H. Seiler,Nathalie Gobeau,Bernard Faller
出处
期刊:ADMET and DMPK
[International Association of Physical Chemists]
日期:2016-03-30
卷期号:4 (1): 35-35
被引量:10
标识
DOI:10.5599/admet.4.1.258
摘要
<p class="ADMETabstracttext">Solubility can be the absorption limiting factor for drug candidates and is therefore a very important input parameter for oral exposure prediction of compounds with limited solubility. Biorelevant media of the fasted and fed state have been published for humans, as well as for dogs in the fasted state. In a drug discovery environment, rodents are the most common animal model to assess the oral exposure of drug candidates. In this study a rat simulated intestinal fluid (rSIF) is proposed as a more physiologically relevant media to describe drug solubility in rats. Equilibrium solubility in this medium was tested as input parameter for physiologically-based pharmacokinetics (PBPK) simulations of oral pharmacokinetics in the rat. Simulations were compared to those obtained using other solubility values as input parameters, like buffer at pH 6.8, human simulated intestinal fluid and a comprehensive dissolution assay based on rSIF. Our study on nine different compounds demonstrates that the incorporation of rSIF equilibrium solubility values into PBPK models of oral drug exposure can significantly improve the reliability of simulations in rats for doses up to 300 mg/kg compared to other media. The comprehensive dissolution assay may help to improve further simulation outcome, but the greater experimental effort as compared to equilibrium solubility may limit its use in a drug discovery environment. Overall, PBPK simulations based on solubility in the proposed rSIF medium can improve prioritizing compounds in drug discovery as well as planning dose escalation studies, e.g. during toxicological investigations.</p>
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