BIOMD0000000320
type: SBMLModel
reaction: 040961
units def: 945531
reaction: 040969
compartment: 040943
occurs in: http://identifiers.org/taxonomy/10116
parameter: 041017
parameter: 041023
is: MODEL0910130001
parameter: 041027
rule: 040997
reaction: 040971
is version of: GO:0051583
compartment: 040946
compartment: 040936
units def: 945507
time units: metaid_0000071
reaction: 040974
area units: area
reaction: 040965
initial assignment: BIOMD0000000320#
species: 040957
notes: Grange2001 - PK interaction of L-dopa and benserazide A pharmacokinetics of L-dopa in rats after administration of L-dopa alone (BIOMD0000000321) or L-dopa combined with a peripheral AADC (amino-acid-decarboxylase) inhibitor (this model: BIOMD0000000320) has been studied using noncompartmental analysis. This model is described in the article: A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats. Grange S, Holford NH, Guentert TW Pharmaceutical Research [2001, 18(8):1174-1184] Abstract: PURPOSE: To study the PK interaction of L-dopa/benserazide in rats. METHODS: Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC. RESULTS: The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC. CONCLUSIONS: Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide. The volumes and variables in this model are taken for a rat with 0.25 kg. The in…
parameter: 041045
parameter: 041041
species: 040947
parameter: 041036
reaction: 040980
parameter: 041021
parameter: 041012
name: Grange2001 - PK interaction of L-dopa and benserazide
volume units: 697232
parameter: 041050
parameter: 041051
units def: metaid_0000071
rule: 041006
rule: 040995
species: 040952
parameter: 041026
rule: 040998
parameter: 041039
rule: 041003
reaction: 040968
parameter: 041054
compartment: 040935
parameter: 041029
parameter: 041030
compartment: 040941
parameter: 041044
units def: 945470
parameter: 041020
species: 040948
curated: true
reaction: 040963
reaction: 040978
rule: 041000
species: 040955
parameter: 041035
parameter: 041009
reaction: 040983
parameter: 041038
rule: 041007
parameter: 041011
parameter: 041014
parameter: 041015
parameter: 041053
is described by: http://identifiers.org/pubmed/11587490
compartment: 040937
species: 040960
reaction: 040962
compartment: 040940
is version of: G20
reaction: 040972
parameter: 041032
parameter: 041033
species: 040949
rule: 041004
reaction: 040981
parameter: 041018
length unit: length

040961
type: Reaction
kinetic law: 945653
product: 945640
reactant: 945628
is version of: GO:0050892
is: SBO:0000185
fast: false
reversible: false
name: L_Dopa absorption from gut

945640
type: SpeciesReference
stoichiometry: 1.0
species: 040951

040951
type: Species
initial amount: NaN
constant: false
is: http://identifiers.org/pubchem.compound/6047
is: C00355
boundary condition: false
is: CHEBI:15765
initial concentration: 0.0
is: SBO:0000247
has only substance units: false
in compartment: 040936

040936
type: Compartment
is version of: FMA:7563
is: SBO:0000290
constant: true
size: 0.496
spatial dimensions: 3.0
name: V_L_Dopa

945628
type: SpeciesReference
stoichiometry: 1.0
species: 040947

040947
type: Species
is: SBO:0000247
is: CHEBI:15765
is: C00355
in compartment: 040935
boundary condition: false
initial amount: NaN
is: http://identifiers.org/pubchem.compound/6047
has only substance units: true
initial concentration: NaN
constant: false

040935
type: Compartment
is version of: BTO:0000648
is: SBO:0000290
constant: true
size: 1.0
spatial dimensions: 3.0

945531
type: SBMLUnitsDef
unit: 945555
unit: 945543
name: l_per_h

945555
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND

945543
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 1.0
kind: LITRE

040969
type: Reaction
is version of: REACT 15382.1
kinetic law: 945798
is version of: http://identifiers.org/ec-code/4.1.1.28
reactant: 945785
is version of: GO:0042737
is: SBO:0000399
name: L-Dopa clearance via AADC
fast: false
reversible: false

945785
type: SpeciesReference
stoichiometry: 1.0
species: 040951

040943
type: Compartment
is version of: FMA:76700
is: SBO:0000290
constant: true
size: 0.0691
spatial dimensions: 3.0

041017
type: Parameter
notes: hepatically cleared fraction of l-dopa
is: SBO:0000381
constant: true
units: dimensionless
value: 0.13

041023
type: Parameter
is: SBO:0000381
constant: true
units: dimensionless
value: 0.1

041027
type: Parameter
notes: catechol-O-methyltransferase mediated L-Dopa clearance
is: SBO:0000035
constant: false
units: 945531
value: NaN

040971
type: Reaction
is version of: GO:0042737
kinetic law: 945834
product: 945822
reactant: 945810
name: L-Dopa clearance via COMT
fast: false
reversible: false
is version of: http://identifiers.org/ec-code/2.1.1.6
is: SBO:0000214

945822
type: SpeciesReference
stoichiometry: 1.0
species: 040952

040952
type: Species
is: SBO:0000247
is: http://identifiers.org/pubchem.compound/9307
boundary condition: false
has only substance units: false
is version of: CHEBI:25212
initial amount: NaN
initial concentration: 0.0
constant: false
in compartment: 040937
name: C_3-OMD

040937
type: Compartment
is version of: FMA:7563
is: SBO:0000290
constant: true
size: 0.128
spatial dimensions: 3.0

945810
type: SpeciesReference
stoichiometry: 1.0
species: 040951

040946
type: Compartment
is version of: FMA:76700
is: SBO:0000290
constant: true
size: 3.2
spatial dimensions: 3.0

945507
type: SBMLUnitsDef
unit: 945519
name: per_h

945519
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND

metaid_0000071
type: SBMLUnitsDef
unit: 945567
name: hours

945567
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 3600.0
kind: SECOND

040974
type: Reaction
kinetic law: 945883
reactant: 945871
has version: GO:0042737
has version: GO:0007588
is: SBO:0000179
fast: false
reversible: false
name: 3-OMD clearance

945871
type: SpeciesReference
stoichiometry: 1.0
species: 040952

040965
type: Reaction
kinetic law: 945749
product: 945737
reactant: 945725
is version of: GO:0050892
is: SBO:0000185
fast: false
reversible: false
name: benserazide absorption from gut

945737
type: SpeciesReference
stoichiometry: 1.0
species: 040957

040957
type: Species
initial amount: NaN
is: D03082
constant: false
in compartment: 040940
initial concentration: 0.0
boundary condition: false
is: http://identifiers.org/pubchem.compound/2327
notes: Benserazide in the central compartment
is: SBO:0000247
has only substance units: false

040940
type: Compartment
is version of: FMA:76700
is: SBO:0000290
constant: true
size: 0.202
spatial dimensions: 3.0

945725
type: SpeciesReference
stoichiometry: 1.0
species: 040948

040948
type: Species
is: http://identifiers.org/pubchem.compound/2327
in compartment: 040935
has only substance units: true
initial amount: NaN
is: SBO:0000247
constant: false
boundary condition: false
initial concentration: NaN
is: D03082

041053
type: Parameter
is: SBO:0000196
constant: true
units: 945445
value: NaN

945445
type: SBMLUnitsDef
unit: 945458
name: micromole

945458
type: SBMLUnit
exponent: 1.0
scale: -9
multipler: 1.0
kind: MOLE

040949
type: Species
initial amount: NaN
is: http://identifiers.org/pubchem.compound/188973
is: SBO:0000247
constant: false
has only substance units: true
boundary condition: false
is version of: CHEBI:25212
initial concentration: NaN
in compartment: 040935

041045
type: Parameter
is: SBO:0000035
constant: true
units: 945531
value: 0.072

041041
type: Parameter
is: SBO:0000035
constant: true
units: 945531
value: 1.67

041036
type: Parameter
notes: absorption rate constant of benserazide
is: SBO:0000035
constant: true
value: 0.94
name: ka_b

040980
type: Reaction
kinetic law: 945968
reactant: 945956
has version: GO:0042737
has version: GO:0007588
is: SBO:0000179
fast: false
reversible: false
name: ro 04-5127 clearance

945956
type: SpeciesReference
stoichiometry: 1.0
species: 040954

040954
type: Species
is: SBO:0000247
is: http://identifiers.org/pubchem.compound/188973
notes: Ro 04-5127, an inhibitor of amino-acid carboxylase (AADC), in the central compartment
in compartment: 040943
boundary condition: false
is version of: CHEBI:25212
initial amount: NaN
has only substance units: false
constant: false
initial concentration: 0.0

041021
type: Parameter
is: SBO:0000381
constant: true
units: dimensionless
value: 0.69

041012
type: Parameter
notes: gastro-intestinal bioavailability of L-Dopa
is: SBO:0000381
constant: true
units: dimensionless
value: 1.0

041050
type: Parameter
is: SBO:0000197
constant: true
units: 945470
value: 78.0

945470
type: SBMLUnitsDef
unit: 945495
unit: 945482
name: micromole_per_kg

945495
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: KILOGRAM

945482
type: SBMLUnit
exponent: 1.0
scale: -9
multipler: 1.0
kind: MOLE

041051
type: Parameter
is: SBO:0000002
constant: true
units: kilogram
value: 0.25

041026
type: Parameter
notes: L-dopa clearance via unspecified elimination pathways
is: SBO:0000035
constant: false
units: 945531
value: NaN

041039
type: Parameter
is: SBO:0000035
constant: true
units: 945531
value: 0.00895
name: CL_3_OMD

040968
type: Reaction
kinetic law: 945773
reactant: 945761
is: GO:0030421
has version: GO:0042737
is: SBO:0000179
fast: false
reversible: false
name: benserazide clearance from gut

945761
type: SpeciesReference
stoichiometry: 1.0
species: 040948

041054
type: Parameter
notes: Ro04-5127 fraction of Bensarazide in gut
is: SBO:0000381
constant: true
value: 0.07
name: Bens_Ro04-5127_fraction_gut

041029
type: Parameter
notes: uninhibited AADC clearance velocity
is: SBO:0000035
constant: false
units: 945531
value: NaN

041030
type: Parameter
is: SBO:0000288
constant: true
value: 0.00246

040941
type: Compartment
is version of: FMA:76700
is: SBO:0000290
constant: true
size: 0.127
spatial dimensions: 3.0

041044
type: Parameter
is: SBO:0000035
constant: true
units: 945531
value: 4.29

041020
type: Parameter
is: SBO:0000381
constant: false
units: dimensionless
value: NaN

040963
type: Reaction
kinetic law: 945713
product: 945701
reactant: 945689
is version of: GO:0050892
is: SBO:0000185
fast: false
reversible: false
name: ro 04-5127 absorption from gut

945701
type: SpeciesReference
stoichiometry: 1.0
species: 040954

945689
type: SpeciesReference
stoichiometry: 1.0
species: 040949

040978
type: Reaction
kinetic law: 945944
product: 945932
reactant: 945920
is version of: GO:0042737
is: SBO:0000211
fast: false
reversible: false
name: benserazide metabolism to ro 04-5127

945932
type: SpeciesReference
stoichiometry: 1.0
species: 040954

945920
type: SpeciesReference
stoichiometry: 1.0
species: 040957

040955
type: Species
in compartment: 040946
initial concentration: 0.0
is version of: CHEBI:25212
initial amount: NaN
boundary condition: false
constant: false
notes: Ro 04-5127 in the peripheral compartment
has only substance units: false
is: http://identifiers.org/pubchem.compound/188973
is: SBO:0000247

041035
type: Parameter
notes: absorption rate constant of Ro 04-5127
is: SBO:0000035
constant: true
value: 2.47
name: ka_m

041009
type: Parameter
notes: bioavailability of L-Dopa
is: SBO:0000381
constant: false
units: dimensionless
value: NaN

040983
type: Reaction
kinetic law: 946040
product: 946028
reactant: 946016
is: SBO:0000185
fast: false
reversible: true
name: ro 04-5127 distribution

946028
type: SpeciesReference
stoichiometry: 1.0
species: 040955

946016
type: SpeciesReference
stoichiometry: 1.0
species: 040954

041038
type: Parameter
notes: oral bioavailability of Benserazide
is: SBO:0000381
constant: true
units: dimensionless
value: 0.022

041011
type: Parameter
notes: hepatic bioavailability of L-Dopa
is: SBO:0000381
constant: false
units: dimensionless
value: NaN

041014
type: Parameter
notes: hepatic blood clearance of L-Dopa
is: SBO:0000035
constant: false
units: 945531
value: NaN

041015
type: Parameter
notes: hepatic blood flow
is: SBO:0000002
constant: true
value: 0.828

040960
type: Species
initial concentration: 0.0
boundary condition: false
has only substance units: false
initial amount: NaN
is: D03082
in compartment: 040941
is: http://identifiers.org/pubchem.compound/2327
is: SBO:0000247
notes: Benserazide in the peripheral compartment
constant: false

040962
type: Reaction
kinetic law: 945677
reactant: 945665
is: GO:0030421
has version: GO:0042737
is: SBO:0000179
fast: false
reversible: false
name: hepatic and blood L-Dopa clearance

945665
type: SpeciesReference
stoichiometry: 1.0
species: 040947

040972
type: Reaction
kinetic law: 945859
reactant: 945846
has version: GO:0007588
has version: GO:0042737
is: SBO:0000179
fast: false
reversible: false
name: rest clearance of L-Dopa

945846
type: SpeciesReference
stoichiometry: 1.0
species: 040951

041032
type: Parameter
notes: total clearance of L-Dopa wo. inhibition
is: SBO:0000035
constant: true
units: 945531
value: 0.823

041033
type: Parameter
notes: absorption rate constant of L_DOPA in the gut
is: SBO:0000035
constant: true
value: 1.29

040981
type: Reaction
kinetic law: 946004
product: 945992
reactant: 945980
is: SBO:0000185
fast: false
reversible: true
name: benserazide distribution

945992
type: SpeciesReference
stoichiometry: 1.0
species: 040960

945980
type: SpeciesReference
stoichiometry: 1.0
species: 040957

041018
type: Parameter
notes: total clearance speed of L-Dopa
is: SBO:0000035
constant: false
units: 945531
value: NaN

040977
type: Reaction
kinetic law: 945908
reactant: 945896
has version: GO:0042737
has version: GO:0007588
is: SBO:0000179
fast: false
reversible: false
name: benserazide clearance

945896
type: SpeciesReference
stoichiometry: 1.0
species: 040957

041042
type: Parameter
is: SBO:0000381
constant: true
units: dimensionless
value: 0.15

041048
type: Parameter
is: SBO:0000197
constant: true
units: 945470
value: 404.0

041024
type: Parameter
notes: L-Dopa clearance by AADC
is: SBO:0000035
constant: false
units: 945531
value: NaN

041047
type: Parameter
is: SBO:0000035
constant: true
units: 945531
value: 1.06

ORG:
  orgname: EMBL-EBI
n:
  given: Vijayalakshmi
  family: Chelliah

W3 CDTF: Mon May 20 15:25:05 BST 2013

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

W3 CDTF: Tue Oct 27 14:45:40 GMT 2009