Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling. Drug Metabolism and Disposition 40(5): 892–901

Abstract

Number of text pages 21 Number of tables 3 Number of figures 4 Number of references 40 Number of words in the abstract 244 DMD #43174 3 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 c ustomized database that was then used to build PBPK models for p ravastatin 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. Number of words in the introduction 715 Number of words in the discussion 1192 List of nonstandard abbreviations DMD #43174