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Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling

Abstract:

Active processes involved in drug metabolization and distribution mediated by enzymes, transporters, or binding partners mostly occur simultaneously in various organs. However, a quantitative description of active processes is difficult because of 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 that 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 that already represent detailed anatomical and physiological information. The new approach was evaluated using three publicly available databases: whole-genome expression microarrays from ArrayExpress, reverse transcription-polymerase chain reaction-derived gene expression estimates collected from the literature, and expressed sequence tags 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 organic anion-transporting polypeptide 1B1 and organic anion transporter 3, active efflux by multidrug resistance protein 2, and metabolization by sulfotransferases in liver, kidney, and/or intestine. Benchmarking of PBPK models based on gene expression data against alternative models with either a less complex model structure or randomly assigned gene expression values clearly demonstrated the superior model performance of the former. Besides 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 because of the physiological representation of protein-mediated processes.

22293118

Projects: G: Clinical translation

Drug Metab. Dispos.
Drug Metab. Dispos. 40(5): 892-901
31st Jan 2012

Michaela Meyer, Sebastian Schneckener, Bernd Ludewig, Lars Kuepfer, Joerg Lippert

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[Lars Küpfer] [Jörg Lippert]

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Views: 2548
  • Created: 27th Apr 2012 at 10:34
  • Last updated: 24th Oct 2013 at 16:17

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