Abstract

Active processes involved in drug metabolization and distribution mediated by enzymes, transporters or binding partners mostly occur simultaneously in various organs. A quantitative description of active processes, however, is difficult due to a limited experimental accessibility of tissue-specific protein activity in vivo. In this work we present a novel approach to estimate in vivo activity of such enzymes or transporters which have an influence on drug pharmacokinetics. Tissue specific mRNA expression is used as a surrogate for protein abundance and activity and is integrated into physiologically-based pharmacokinetic (PBPK) models which already represent detailed anatomical and physiological information. The new approach was evaluated using three publicly available databases: Whole genome expression microarrays from ArrayExpress, RT-PCR derived gene expression estimates collected from literature, and expressed sequence tags (EST) from UniGene. Expression data were preprocessed and stored in a customized database that was then used to build PBPK models for pravastatin in humans. These models represented drug uptake by OATP1B1 and OAT3, active efflux by MRP2, and metabolization by sulfotransferases in either liver, kidney and/or intestine. Bench-marking of PBPK models based on gene expression data against alternative models with either less complex model structure or randomly assigned gene expression values clearly demonstrated the superior model performance of the former. Besides an accurate prediction of drug pharmacokinetics, integration of relative gene expression data in PBPK models offers the unique possibility to simultaneously investigate drug-drug interactions in all relevant organs due to the physiological representation of protein mediated processes.