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notes: This is the model of atorvastatin metabolism in hepaitc cells described in the article: A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes Joachim Bucher , Stephan Riedmaier , Anke Schnabel , Katrin Marcus , Gabriele Vacun , Thomas S Weiss , Wolfgang E Thasler , Andreas K Nussler , Ulrich M Zanger and Matthias Reuss. BMC Systems Biology 2011, 5:66. DOI: 10.1186/1752-0509-5-66 Abstract: Background: The individual character of pharmacokinetics is of great importance in the risk assessment of new drug leads in pharmacological research. Amongst others, it is severely influenced by the properties and inter-individual variability of the enzymes and transporters of the drug detoxification system of the liver. Predicting individual drug biotransformation capacity requires quantitative and detailed models. Results: In this contribution we present the de novo deterministic modeling of atorvastatin biotransformation based on comprehensive published knowledge on involved metabolic and transport pathways as well as physicochemical properties. The model was evaluated in primary human hepatocytes and parameter identifiability analysis was performed under multiple experimental constraints. Dynamic simulations of atorvastatin biotransformation considering the inter-individual variability of the two major involved enzymes CYP3A4 and UGT1A3 based on quantitative protein expression data in a large human liver bank (n=150) highlighted the variability in the individual biotransformation profiles and therefore also points to the individuality of pharmacokinetics. Conclusions: A dynamic model for the biotransformation of atorvastatin has been developed using quantitative metabolite measurements in primary human hepatocytes. The model comprises kinetics for transport processes and metabolic enzymes as well as population liver expression data allowing us to assess the impact of inter-individual variability of concentra…
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W3 CDTF: Fri Mar 09 15:58:34 GMT 2012

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ORG:
  orgname: Institute of Biochemical Engineering, University of Stuttgart, Stuttgart, Germany
n:
  given: Joachim
  family: Bucher

ORG:
  orgname: EMBL-EBI
n:
  given: Lukas
  family: Endler

W3 CDTF: Wed May 11 21:30:58 BST 2011