Vivo High Throughput Screening

Walker SL, Ariga J, Mathias JR, Coothankandaswamy V, Xie X, Distel M, Koster RW, Parsons MJ, Bhalla KN, Saxena MT, Mumm JS (2012) Automated reporter quantification in vivo high-throughput screening method for reporter-based assays in zebrafish. PLoS One, 7, e29916. 

Compared to in vivo studies, the Caco-2 model substantially increases the speed at which absorption potential can be estimated and reduces the amount of drug substance needed. However, manually performed assays are still too slow and labor intensive compared to biological high-throughput screening assays. Caco-2 cells take about 3 weeks to form monolayers of fully differentiated cells. At this point, Caco-2 monolayers are used to evaluate absorption potential under a variety of permeability protocols. In order to further expedite the process of absorption potential assessment, efforts have been made to increase the throughput of Caco-2 transport experiments. 

Cox, K. A. White, R. E. Korfmacher, W. A. Rapid determination of pharmacokinetic properties of new chemical entities in vivo approaches. Comb Chem High Throughput Screen 2002, 5, 29-37. 

Such examples extend PBPK simulations to prediction of target effect and appear very powerful for generation of insights into the efficacy/lack of efficacy in vivo in relation to receptor occupancy. Consequently, such PBPK/PD simulations can be used as a filter between high-throughput screening and in vivo efficacy in order to prioritize compounds expected to be active in vivo. 

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