Transport screening of drug cocktails through an in vitro blood-brain barrier: is it a good strategy for increasing the throughput of the discovery pipeline?

PURPOSE: The objective of the current study was to investigate whether blood-brain barrier (BBB) permeability studies in vitro could be accelerated by running several compounds together in the same experiment.
METHODS: To address this question, we compared the transport of six compounds run separately with the results of the same compounds run together (cocktails).
RESULTS: The study clearly demonstrated that the outcome of the experiments were totally different depending on the strategy used. Furthermore, the study highlights the importance of having the resistance to drug transport offered by filters without cells under control, as the filter membrane itself can be the rate-limiting step for some compounds; in addition, there is always a potential risk of interactions between molecules in cocktails as well as drug-drug interaction at the level of BBB transporters. In this study, the presence of several P-glycoprotein substrates in the drug cocktail was found to cause breakdown of the BBB.
CONCLUSIONS: The results demonstrate that unless a strategy that involves running several compounds in the same experiment is properly validated, the results are of little predictive value.