Kristine Langthaler, Christopher R Jones, Lasse Saaby, Christoffer Bundgaard, Birger Brodin
INTRO: Reliable estimates of drug uptake from blood to brain parenchyma are crucial in CNS drug discovery and development. While in vivo K estimates are the gold standard for investigating brain drug disposition, animal usage is a limitation to high throughput application. This study investigates an in vitro model using P-gp expressing MDCKII-MDR1 cells for predicting in vivo brain drug penetration.
METHODS: In vitro equilibrium distribution studies were conducted in apical and basolateral solutions with high protein content to estimate K and K values. The correlation between in vitro and in vivo K values for a set of compounds was examined.
RESULTS: We observed a good correlation between in vitro and in vivo K values (R���=���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.
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 K 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.
