Open Access Highly Accessed Research article

A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes

Joachim Bucher17, Stephan Riedmaier2, Anke Schnabel3, Katrin Marcus3, Gabriele Vacun18, Thomas S Weiss4, Wolfgang E Thasler5, Andreas K Nüssler6, Ulrich M Zanger2 and Matthias Reuss1*

Author Affiliations

1 Institute of Biochemical Engineering, Allmandring 31, and Center Systems Biology, Nobelstraße 15, University of Stuttgart, 70569 Stuttgart, Germany

2 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstraße 112, 70376 Stuttgart, and University of Tübingen, 72074 Tübingen, Germany

3 Dep. Functional Proteomics, Medizinisches Proteom-Center, Ruhr-University Bochum, Universitätsstraße 150, 44801 Bochum, Germany

4 Department of Surgery, University of Regensburg, F.J.S. Allee 11, 93053 Regensburg, Germany

5 Department of Surgery, Ludwig-Maximilians-University, Marchioninistraße 15, 81377 München, Germany

6 Department of Traumatology, Technical University of Munich, MRI, Ismaningerstraße 22, 81675 Munich, Germany

7 Insilico Biotechnology AG, Meitnerstraße 8, 70563 Stuttgart, Germany

8 Fraunhofer Institut für Grenzflächen und Bioverfahrenstechnik, 70569 Stuttgart, Germany

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BMC Systems Biology 2011, 5:66  doi:10.1186/1752-0509-5-66

Published: 6 May 2011

Additional files

Additional file 1:

Derivation of atorvastatin kinetics at CYP3A4. This file contains the derivation of the atorvastatin kinetics at CYP3A4, which describes the competition of alternative substrate degradation to alternative products (supplemented as .pdf-file).

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Additional file 2:

Derivation of kinetics of unspecific binding to macromolecules. This file contains the derivation of kinetics of the unspecific binding of atorvastatin metabolites to macromolecules, for example proteins (supplemented as .pdf-file).

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Additional file 3:

Atorvastatin metabolite concentrations from the time-series experiment on primary human hepatocytes of individual 1. Extracellular concentrations (upper part) and intracellular concentrations (lower part) of atorvastatin acid and lactone (AS and ASL) and corresponding para- and ortho-hydroxy-metabolites (acids: ASpOH and ASoOH; lactones: ASLpOH and ASLoOH) at the defined time-points with mean and standard deviation (n = 3) from triplicate measurements per LC-MS/MS (n.d.: not determinable; n.o.: not observed). The recovery is calculated from material balance equations and is defined as the sum of intracellular and extracellular metabolite amounts at the respective time-point divided by initial AS amount (supplemented as .pdf-file).

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Additional file 4:

Analysis of parameter sensitivity and following model reduction procedure. This file contains the analysis of parameter sensitivity and the exemplary model reduction procedure, which is necessary for achieving a high quality predictive model of atorvastatin metabolism (supplemented as .pdf-file).

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Additional file 5:

Atorvastatin metabolite concentrations from the time-series experiment on primary human hepatocytes of individual 2. Extracellular concentrations (upper part) and intracellular concentrations (lower part) of atorvastatin acid and lactone (AS and ASL) and corresponding para- and ortho-hydroxy-metabolites (acids: ASpOH and ASoOH; lactones: ASLpOH and ASLoOH) at the defined time-points with mean and standard deviation (n = 3) from triplicate measurements per LC-MS/MS (n.d.: not determinable) (supplemented as .pdf-file).

Format: PDF Size: 9KB Download file

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Additional file 6:

Atorvastatin metabolite concentrations from the time-series experiment on primary human hepatocytes of individual 3. Extracellular concentrations (upper part) and intracellular concentrations (lower part) of atorvastatin acid and lactone (AS and ASL) and corresponding para- and ortho-hydroxy-metabolites (acids: ASpOH and ASoOH; lactones: ASLpOH and ASLoOH) at the defined time-points with mean and standard deviation (n = 3) from triplicate measurements per LC-MS/MS (n.d.: not determinable) (supplemented as .pdf-file).

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Additional file 7:

Model of atorvastatin metabolism in primary human hepatocytes of individual 1. The sbml-file contains the model of Atorvastatin metabolism in human hepatocytes with the model parameters identified on primary human hepatocytes of individual 1 (supplemented as .xml-file).

Format: XML Size: 136KB Download file

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