Conclusion
The in vitro assay setup developed in this study holds promise for predicting in vivo drug brain penetration in CNS drug discovery. The correlation between in vitro and in vivo Kp,brain values, underscores that the model may have potential for early-stage screening. With minor refinements, this in vitro approach could reduce the reliance on in vivo experiments, accelerating the pace of CNS drug discovery and promoting a more ethical research approach.
Methods
In vitro equilibrium distribution studies were conducted in apical and basolateral solutions with high protein content to estimate Kp,brain and Kp,uu,brain values. The correlation between in vitro and in vivo Kp,brain values for a set of compounds was examined.
Results
We observed a good correlation between in vitro and in vivo Kp,brain values (R2 = 0.69, Slope: 1.6), indicating that the in vitro model could predict in vivo drug brain penetration. The 'unilateral (Uni-L)' in vitro setup correctly classified 5 out of 5 unrestricted compounds and 3 out of 5 restricted compounds. Possible reasons for the observed disparities for some compounds have been discussed, such as difference in transport areas between in vitro and in vivo settings and effect of pH changes.