Advances in physiologically based modeling coupled with in vitro-in vivo extrapolation of ADMET: Assessing the impact of genetic variability in hepatic transporters

In the recent years, many European health agencies strongly support the development of PBTK models, which may provide quantitative descriptions of the ADMET processes of environmental or pharmaceutical chemicals. Research studies have revealed the importance of transporter activity and substrate affinity to transporters and metabolizing enzymes for the regulation of substrate disposition in man. Population differences in active hepatic transport caused by polymorphism may provide answers to some of the interindividual variability in the toxicokinetics of xenobiotics. In vitro assays coupled with in silico methods, such as physiologically based pharmacokinetic (PBPK) modeling, can, through in vitro-in vivo extrapolation, provide high-throughput screening of toxicological and pharmacological entities, with the potential of saving time, cost, and minimizing animal research. In a case example, the use of in vitro pharmacokinetic data to demonstrate the potential interindividual variability in the toxicological effect as a function of active hepatic uptake transport of statins through PBPK modeling and simulation was described.