Evaluation indexes of blood-brain barrier in Kp,uu-CNS drugs

Only the concentration of free CNS drugs at the therapeutic target can play a pharmacological role, and the concentration of free CNS drugs in the brain has a good correlation with clinical effects or brain side effects.

Kp,uu: ratio of brain free drugs to plasma free drugs. Good Kp and uu characteristics are more conducive to reflecting the advantages of candidate compounds as CNS drugs. Kp and uu can not only evaluate the degree of drug entry into the blood-brain barrier, but also quantitatively predict potential drug interactions (occurring in central nervous system interactions). The size of the interaction depends on whether the Kp,uu can be reversed. If there is no active transport in the blood-brain barrier, the Kp,uu value is close to 1 (i.e. the ISF in the brain is equal to the free blood concentration), there is no risk of interaction. The higher the efflux efficiency of the blood-brain barrier, the lower the Kp and uu values, and the greater the risk of interaction. In CNS projects, PCC compound Kp is generally obtained at last, with uu above 0.5.

Tissue homogenization: The unbound portion of ICF and ISF cannot be distinguished because the process of tissue homogenization disrupts cell integrity and does not account for active cell uptake or Ph-dependent distribution across cell membranes.

Microdialysis: The gold standard for determining the free portion of ISF, the free portion of ICF cannot be obtained. Microdialysis membrane aperture is generally 20kD, less than 3kD to be measured is easy to diffuse. For drugs and lipophilic compounds with molecular weight greater than 3kD, membrane pore size with molecular interception value >100kD or greater should be used, but the experimental bias caused by pipe adsorption and membrane pore inapplicability should be avoided as much as possible.

Histography: Kpuu,cell can be measured to evaluate the free part of the cell. The following formula is used for calculation.