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BIOMD0000000328 - Bucher2011_Atorvastatin_Metabolism

 

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Reference Publication
Publication ID: 21548957
Bucher J, Riedmaier S, Schnabel A, Marcus K, Vacun G, Weiss TS, Thasler WE, N├╝ssler AK, Zanger UM, Reuss M.
A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes.
BMC Syst Biol 2011; 5: 66
Institute of Biochemical Engineering, Allmandring, and Center Systems Biology, Nobelstra├če, University of Stuttgart, Germany.  [more]
Model
Original Model: BIOMD0000000328.origin
Submitter: Joachim Bucher
Submission ID: MODEL1103200000
Submission Date: 20 Mar 2011 17:34:31 UTC
Last Modification Date: 08 Apr 2016 18:00:25 UTC
Creation Date: 11 May 2011 21:30:58 UTC
Encoders:  Lukas Endler
   Joachim Bucher
set #1
bqbiol:hasProperty Human Disease Ontology cholesterol embolism
Human Disease Ontology heart disease
set #2
bqbiol:isVersionOf Gene Ontology cholesterol catabolic process
Gene Ontology response to statin
set #3
bqbiol:hasTaxon Taxonomy Homo sapiens
set #4
bqbiol:occursIn Brenda Tissue Ontology hepatocyte
set #5
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
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 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.

The model is parameterized for patient 1 and reproduces the time courses in figure 2 of the article.

Model
Publication ID: 21548957 Submission Date: 20 Mar 2011 17:34:31 UTC Last Modification Date: 08 Apr 2016 18:00:25 UTC Creation Date: 11 May 2011 21:30:58 UTC
Mathematical expressions
Reactions
Import_AS Import_ASL CYP3A4_ASpOH CYP3A4_ASoOH
CYP3A4_ASLpOH CYP3A4_ASLoOH Export_ASoOH UGT1A3_AS
R_ASASL_c CR_oOH CR_pOH Export_AS
Export_ASL Import_ASLpOH Import_ASLoOH ASpOH_Prot
ASoOH_Prot ASLpOH_Prot ASLoOH_Prot AS_Prot
ASL_Prot Import_ASpOH R_ASASL_m R_pOH_m
R_oOH_m Export_ASLpOH Export_ASLoOH Export_ASpOH
Import_ASoOH      
Physical entities
Compartments Species
compartment      
medium AS_m ASL_m ASoOH_m
ASLpOH_m ASpOH_m ASLoOH_m
     
cell AS_c ASL_c ASpOH_c
ASoOH_c ASLpOH_c ASLoOH_c
ASpOH_b ASoOH_b ASLpOH_b
ASLoOH_b AS_b ASL_b
Global parameters
CYP3A4_ASLpOH_Km1 CYP3A4_ASLoOH_Km1 CYP3A4_ASpOH_Km1 CYP3A4_ASoOH_Km1
Import_ASLpOH_k Import_ASLoOH_k Import_ASL_k fu_ASL
fu_AS Import_ASpOH_k Export_ASLpOH_k Export_ASLoOH_k
k_CR_ASL_c k_CR_ASL_m k_PON_OH_c Export_ASoOH_k
Prot_k1 CYP3A4_ASoOH_Vmax CYP3A4_ASLpOH_Vmax CYP3A4_ASLoOH_Vmax
UGT1A3_AS_Vmax UGT1A3_AS_Km1 UGT1A3_AS_KI1 k_PON_ASL_c
Export_AS_k Export_ASL_k Import_AS_k Import_ASoOH_k
Export_ASpOH_k CYP3A4_ASpOH_Vmax    
Reactions (29)
 
 Import_AS [AS_m] → [AS_c];  
 
 Import_ASL [ASL_m] → [ASL_c];  
 
 CYP3A4_ASpOH [AS_c] → [ASpOH_c];   {ASL_c}
 
 CYP3A4_ASoOH [AS_c] → [ASoOH_c];   {ASL_c}
 
 CYP3A4_ASLpOH [ASL_c] → [ASLpOH_c];   {AS_c}
 
 CYP3A4_ASLoOH [ASL_c] → [ASLoOH_c];   {AS_c}
 
 Export_ASoOH [ASoOH_c] → [ASoOH_m];  
 
 UGT1A3_AS [AS_c] → [ASL_c];  
 
 R_ASASL_c [ASL_c] → [AS_c];  
 
 CR_oOH [ASLoOH_c] → [ASoOH_c];  
 
 CR_pOH [ASLpOH_c] → [ASpOH_c];  
 
 Export_AS [AS_c] → [AS_m];  
 
 Export_ASL [ASL_c] → [ASL_m];  
 
 Import_ASLpOH [ASLpOH_m] → [ASLpOH_c];  
 
 Import_ASLoOH [ASLoOH_m] → [ASLoOH_c];  
 
 ASpOH_Prot [ASpOH_c] → [ASpOH_b];  
 
 ASoOH_Prot [ASoOH_c] → [ASoOH_b];  
 
 ASLpOH_Prot [ASLpOH_c] → [ASLpOH_b];  
 
 ASLoOH_Prot [ASLoOH_c] → [ASLoOH_b];  
 
 AS_Prot [AS_c] → [AS_b];  
 
 ASL_Prot [ASL_c] → [ASL_b];  
 
 Import_ASpOH [ASpOH_m] → [ASpOH_c];  
 
 R_ASASL_m [ASL_m] → [AS_m];  
 
 R_pOH_m [ASLpOH_m] → [ASpOH_m];  
 
 R_oOH_m [ASLoOH_m] → [ASoOH_m];  
 
 Export_ASLpOH [ASLpOH_c] → [ASLpOH_m];  
 
 Export_ASLoOH [ASLoOH_c] → [ASLoOH_m];  
 
 Export_ASpOH [ASpOH_c] → [ASpOH_m];  
 
 Import_ASoOH [ASoOH_m] → [ASoOH_c];  
 
  Spatial dimensions: 3.0  Compartment size: 1.0
  Spatial dimensions: 3.0  Compartment size: 2.0
 
 AS_m
Compartment: medium
Initial concentration: 8797.15
 
 ASL_m
Compartment: medium
Initial concentration: 30.56
 
 ASoOH_m
Compartment: medium
Initial concentration: 0.0
 
 ASLpOH_m
Compartment: medium
Initial concentration: 0.0
 
 ASpOH_m
Compartment: medium
Initial concentration: 0.0
 
 ASLoOH_m
Compartment: medium
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 0.0142
 
 AS_c
Compartment: cell
Initial concentration: 0.0
 
 ASL_c
Compartment: cell
Initial concentration: 0.0
 
 ASpOH_c
Compartment: cell
Initial concentration: 0.0
 
 ASoOH_c
Compartment: cell
Initial concentration: 0.0
 
 ASLpOH_c
Compartment: cell
Initial concentration: 0.0
 
 ASLoOH_c
Compartment: cell
Initial concentration: 0.0
 
 ASpOH_b
Compartment: cell
Initial concentration: 0.0
 
 ASoOH_b
Compartment: cell
Initial concentration: 0.0
 
 ASLpOH_b
Compartment: cell
Initial concentration: 0.0
 
 ASLoOH_b
Compartment: cell
Initial concentration: 0.0
 
 AS_b
Compartment: cell
Initial concentration: 0.0
 
 ASL_b
Compartment: cell
Initial concentration: 0.0
 
Global Parameters (30)
 
 CYP3A4_ASLpOH_Km1
Value: 1400.0   (Units: pmole per ml)
Constant
 
 CYP3A4_ASLoOH_Km1
Value: 3900.0   (Units: pmole per ml)
Constant
 
 CYP3A4_ASpOH_Km1
Value: 25600.0   (Units: pmole per ml)
Constant
 
 CYP3A4_ASoOH_Km1
Value: 29700.0   (Units: pmole per ml)
Constant
 
 Import_ASLpOH_k
Value: 0.033729   (Units: ml per minute)
Constant
 
 Import_ASLoOH_k
Value: 0.026122   (Units: ml per minute)
Constant
 
 Import_ASL_k
Value: 0.2754   (Units: ml per minute)
Constant
 
 fu_ASL
Value: 0.22   (Units: dimensionless)
Constant
 
 fu_AS
Value: 0.22   (Units: dimensionless)
Constant
 
 Import_ASpOH_k
Value: 0.0039614   (Units: ml per minute)
Constant
 
 Export_ASLpOH_k
Value: 0.0011319   (Units: ml per minute)
Constant
 
 Export_ASLoOH_k
Value: 0.0026674   (Units: ml per minute)
Constant
 
 k_CR_ASL_c
Value: 3.55E-5   (Units: ml per minute)
Constant
 
 k_CR_ASL_m
Value: 0.005   (Units: ml per minute)
Constant
 
 k_PON_OH_c
Value: 0.0039829   (Units: ml per minute)
Constant
 
 Export_ASoOH_k
Value: 0.0015983   (Units: ml per minute)
Constant
 
 Prot_k1
Value: 8.52   (Units: ml per minute)
Constant
 
 CYP3A4_ASoOH_Vmax
Value: 47.4985   (Units: pmole per minute)
Constant
 
 CYP3A4_ASLpOH_Vmax
Value: 17.4446   (Units: pmole per minute)
Constant
 
 CYP3A4_ASLoOH_Vmax
Value: 39.1342   (Units: pmole per minute)
Constant
 
 UGT1A3_AS_Vmax
Value: 13.5862   (Units: pmole per minute)
Constant
 
 UGT1A3_AS_Km1
Value: 12000.0   (Units: pmole per ml)
Constant
 
 UGT1A3_AS_KI1
Value: 75000.0   (Units: pmole per ml)
Constant
 
 k_PON_ASL_c
Value: 0.0043734   (Units: ml per minute)
Constant
 
 Export_AS_k
Value: 0.002166   (Units: ml per minute)
Constant
 
 Export_ASL_k
Value: 0.021822   (Units: ml per minute)
Constant
 
 Import_AS_k
Value: 0.020335   (Units: ml per minute)
Constant
 
 Import_ASoOH_k
Value: 3.8875E-4   (Units: ml per minute)
Constant
 
 Export_ASpOH_k
Value: 7.9526E-4   (Units: ml per minute)
Constant
 
 CYP3A4_ASpOH_Vmax
Value: 15.7336   (Units: pmole per minute)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000328

Curator's comment: (updated: 09 May 2011 04:45:43 GMT)

Time courses as in figure 2 of the publication. Integration was performed using Copasi 4.6.33.

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