title: A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes.
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 on 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 concentrations of key proteins. Application of computational tools for parameter sensitivity analysis enabled us to considerably improve the validity of the model and to create a consistent framework for precise computer-aided simulations in toxicology.
authors.affiliation: Institute of Biochemical Engineering, Allmandring, and Center Systems Biology, Nobelstraße, University of Stuttgart, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Bucher
authors.forename: Stephan
authors.initials: S
authors.lastname: Riedmaier
authors.forename: Anke
authors.initials: A
authors.lastname: Schnabel
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.forename: Gabriele
authors.initials: G
authors.lastname: Vacun
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nüssler
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Matthias
authors.initials: M
authors.lastname: Reuss
mesh_terms: D000069059:Atorvastatin; D001692:Biological Transport; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006538:Heptanoic Acids / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007783:Lactones / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008954:Models, Biological; D011758:Pyrroles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D049490:Systems Biology / Q000379:methods*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D011758:Pyrroles; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C122075:UDP-glucuronosyltransferase, UGT1A3; D014453:Glucuronosyltransferase