Zhao Rong, Kalvass J Cory, Pollack Gary M
Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Pharm Res. 2009 Jul;26(7):1657-64. doi: 10.1007/s11095-009-9876-4. Epub 2009 Apr 22.
To assess the blood-brain barrier (BBB) permeability of 12 clinically-used drugs in mdr1a(+/+) and mdr1a(-/-) mice, and investigate the influence of lipophilicity, nonspecific brain tissue binding, and P-gp-mediated efflux on the rate of brain uptake.
The BBB partition coefficient (PS) was determined using the in situ mouse brain perfusion technique. The net brain uptake for 12 compounds, and the time course of brain uptake for selected compounds ranging in BBB equilibration kinetics from rapidly-equilibrating (e.g., alfentanil, sufentanil) to slowly-equilibrating (fexofenadine), was determined and compared.
There was a sigmoidal relationship in mdr1a(-/-) mice between the log-PS and clogD(7.4) in the range of 0-5. The brain uptake clearance was a function of both permeability and blood flow rate. The brain unbound fraction was inversely proportional to lipophilicity. Alfentanil achieved brain equilibrium approximately 4,000-fold faster than fexofenadine, based on the magnitude of PSxfu,brain.
In situ brain perfusion is a useful technique to determine BBB permeability. Lipophilicity, ionization state, molecular weight and polar surface area are all important determinants for brain penetration. The time to blood-to-brain equilibrium varies widely for different compounds, and is determined by a multiplicity of pharmacokinetic factors.
评估12种临床常用药物在mdr1a(+/+)和mdr1a(-/-)小鼠中的血脑屏障（BBB）通透性，并研究亲脂性、非特异性脑组织结合以及P-糖蛋白介导的外排对脑摄取速率的影响。
采用原位小鼠脑灌注技术测定BBB分配系数（PS）。测定并比较了12种化合物的脑净摄取量，以及从快速平衡（如阿芬太尼、舒芬太尼）到缓慢平衡（非索非那定）的不同BBB平衡动力学的选定化合物的脑摄取时间进程。
在mdr1a(-/-)小鼠中，log-PS与clogD(7.4)在0-5范围内呈S形关系。脑摄取清除率是通透性和血流速率的函数。脑未结合分数与亲脂性成反比。基于PSxfu,brain的大小，阿芬太尼达到脑平衡的速度比非索非那定快约4000倍。
原位脑灌注是测定BBB通透性的有用技术。亲脂性、离子化状态、分子量和极性表面积都是脑渗透的重要决定因素。不同化合物从血到脑达到平衡的时间差异很大，并且由多种药代动力学因素决定。
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