An integrated reactive metabolite evaluation approach to assess and reduce safety risk during drug discovery and development.

Metabolic bioactivation is widely considered an undesirable event and a likely prerequisite step in the expression of drug-induced hepatotoxicity and hypersensitivity. Reducing bioactivation risk early in drug discovery, therefore, may help reduce compound attrition and provide safer drug therapies. In vitro bioactivation data and clinical dose for a large set of marketed drugs were analysed for their concordance with clinical hepatotoxicity and the data used to develop an early reactive metabolite strategy.

Directional trans-epithelial transport of organic anions in porcine LLC-PK1 cells that co-express human OATP1B1 (OATP-C) and MRP2.

The transcellular transport of many compounds, which cannot readily cross the lipid bilayer, is mediated by drug uptake and efflux transporters. Human OATP1B1 and MRP2 have been implicated in the hepato-biliary transport of many endogenous and exogenous compounds. Here, we have established epithelial porcine kidney LLC-PK1 derived cell lines, that express both transporters in a polarized fashion, as a model to predict hepato-biliary transport.

Endogenous drug transporters in in vitro and in vivo models for the prediction of drug disposition in man.

The epithelial canine and porcine kidney cell lines MDCK, MDCKII and LLC-PK1, respectively are employed to establish recombinant models of drug transport. Endogenous drug carriers in these cells may contribute to the activities of recombinant drug transporters, thus making it difficult to assess their properties. We analysed the expression of endogenous transporters in these cell lines by RT-PCR and by determining drug transporter activities.