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BIOMD0000000320 - Grange2001 - PK interaction of L-dopa and benserazide

 

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Reference Publication
Publication ID: 11587490
Grange S, Holford NH, Guentert TW.
A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats.
Pharm. Res. 2001 Aug; 18(8): 1174-1184
PRNS Non-Clinical Drug Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland. susan.grange@roche.com  [more]
Model
Original Model: BIOMD0000000320.origin
Submitter: Lukas Endler
Submission ID: MODEL0910130001
Submission Date: 29 Oct 2009 17:40:51 UTC
Last Modification Date: 10 Oct 2014 11:18:15 UTC
Creation Date: 27 Oct 2009 14:45:40 UTC
Encoders:  Lukas Endler
   Vijayalakshmi Chelliah
set #1
bqbiol:hasProperty Human Disease Ontology DOID:14330
set #2
bqbiol:occursIn Taxonomy Rattus norvegicus
bqbiol:isVersionOf ICD Parkinson disease
Gene Ontology dopamine uptake involved in synaptic transmission
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:

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 inital dose for L_Dopa (L_Dopa_per_kg_rat) and Benserazide (Benserazide_per_kg_rat) are to be given in umole per kg. 80 mg/kg L-Dopa correspond to 404 umol/kg, 20 mg/kg benserazide to 78 umol/kg. To change the model to a different mass of rat the compartment volumes, and the parameters rat_body_mass and Q have to changed accordingly.

The model has three species (A-dopa, A_B, A_M) whose initial concentrations are calculated from a listOfInitialAssignments . While running for the first time the time-course (24hrs) for this model in COPASI (up to version 4.6, Build 33), the resulting graph displays only straight lines for all the species. Any subsequent runs should provide proper plots (i.e. without making any change to the model, just by clicking the "run" button again).

The above issue is caused by some initial assignments which are not calculated when COPASI imports the file. This issue should not be present in newer releases of COPASI.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 11587490 Submission Date: 29 Oct 2009 17:40:51 UTC Last Modification Date: 10 Oct 2014 11:18:15 UTC Creation Date: 27 Oct 2009 14:45:40 UTC
Mathematical expressions
Reactions
L_Dopa absorption from gut hepatic and blood L-Dopa clearance ro 04-5127 absorption from gut benserazide absorption from gut
benserazide clearance from gut L-Dopa clearance via AADC L-Dopa clearance via COMT rest clearance of L-Dopa
3-OMD clearance benserazide clearance benserazide metabolism to ro 04-5127 ro 04-5127 clearance
benserazide distribution ro 04-5127 distribution    
Rules
Assignment Rule (variable: F_c) Assignment Rule (variable: F_H) Assignment Rule (variable: CL_H) Assignment Rule (variable: CL_dopa)
Assignment Rule (variable: f_rest) Assignment Rule (variable: CL_AADC) Assignment Rule (variable: CL_rest) Assignment Rule (variable: CL_COMT)
Assignment Rule (variable: CL_AADC0)      
Physical entities
Compartments Species
gut A_dopa A_B A_M
     
V_L_Dopa C_dopa    
V_3_OMD C_3-OMD    
V1_B C1_B    
V2_B C2_B    
V1_M C1_M    
V2_M C2_M    
Global parameters
F_c F_H F_G CL_H
Q f_H CL_dopa f_rest
f_AADC f_COMT CL_AADC CL_rest
CL_COMT CL_AADC0 ki CL_dopa0
ka_c ka_m ka_b F_B
CL_3_OMD CL_B fm CL_M
CL_dB CL_dM L_Dopa_per_kg_rat Benserazide_per_kg_rat
rat_body_mass A_bens_tot Bens_Ro04-5127_fraction_gut  
Reactions (14)
 
 L_Dopa absorption from gut [A_dopa] → [C_dopa];  
 
 hepatic and blood L-Dopa clearance [A_dopa] → ;  
 
 ro 04-5127 absorption from gut [A_M] → [C1_M];  
 
 benserazide absorption from gut [A_B] → [C1_B];  
 
 benserazide clearance from gut [A_B] → ;  
 
 L-Dopa clearance via AADC [C_dopa] → ;  
 
 L-Dopa clearance via COMT [C_dopa] → [C_3-OMD];  
 
 rest clearance of L-Dopa [C_dopa] → ;  
 
 3-OMD clearance [C_3-OMD] → ;  
 
 benserazide clearance [C1_B] → ;  
 
 benserazide metabolism to ro 04-5127 [C1_B] → [C1_M];  
 
 ro 04-5127 clearance [C1_M] → ;  
 
 benserazide distribution [C1_B] ↔ [C2_B];  
 
 ro 04-5127 distribution [C1_M] ↔ [C2_M];  
 
Rules (9)
 
 Assignment Rule (name: F_c) F_c = F_H*F_G
 
 Assignment Rule (name: F_H) F_H = 1-CL_H/Q
 
 Assignment Rule (name: CL_H) CL_H = f_H*CL_dopa
 
 Assignment Rule (name: CL_dopa) CL_dopa = CL_AADC+CL_rest+CL_COMT
 
 Assignment Rule (name: f_rest) f_rest = 1-(f_AADC+f_COMT)
 
 Assignment Rule (name: CL_AADC) CL_AADC = CL_AADC0/(1+C1_M/ki)
 
 Assignment Rule (name: CL_rest) CL_rest = CL_dopa0*f_rest
 
 Assignment Rule (name: CL_COMT) CL_COMT = CL_dopa0*f_COMT
 
 Assignment Rule (name: CL_AADC0) CL_AADC0 = CL_dopa0*f_AADC
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 A_dopa
Compartment: gut
 
 A_B
Compartment: gut
 
 A_M
Compartment: gut
 
 V_L_Dopa Spatial dimensions: 3.0  Compartment size: 0.496
 
 C_dopa
Compartment: V_L_Dopa
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 0.128
 
 C_3-OMD
Compartment: V_3_OMD
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 0.202
 
 C1_B
Compartment: V1_B
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 0.127
 
 C2_B
Compartment: V2_B
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 0.0691
 
 C1_M
Compartment: V1_M
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 3.2
 
 C2_M
Compartment: V2_M
Initial concentration: 0.0
 
Global Parameters (31)
 
  F_c
Value: NaN   (Units: dimensionless)
 
  F_H
Value: NaN   (Units: dimensionless)
 
 F_G
Value: 1.0   (Units: dimensionless)
Constant
 
  CL_H
Value: NaN   (Units: l_per_h)
 
 Q
Value: 0.828
Constant
 
 f_H
Value: 0.13   (Units: dimensionless)
Constant
 
  CL_dopa
Value: NaN   (Units: l_per_h)
 
  f_rest
Value: NaN   (Units: dimensionless)
 
 f_AADC
Value: 0.69   (Units: dimensionless)
Constant
 
 f_COMT
Value: 0.1   (Units: dimensionless)
Constant
 
  CL_AADC
Value: NaN   (Units: l_per_h)
 
  CL_rest
Value: NaN   (Units: l_per_h)
 
  CL_COMT
Value: NaN   (Units: l_per_h)
 
  CL_AADC0
Value: NaN   (Units: l_per_h)
 
 ki
Value: 0.00246
Constant
 
 CL_dopa0
Value: 0.823   (Units: l_per_h)
Constant
 
 ka_c
Value: 1.29
Constant
 
 ka_m
Value: 2.47
Constant
 
 ka_b
Value: 0.94
Constant
 
 F_B
Value: 0.022   (Units: dimensionless)
Constant
 
 CL_3_OMD
Value: 0.00895   (Units: l_per_h)
Constant
 
 CL_B
Value: 1.67   (Units: l_per_h)
Constant
 
 fm
Value: 0.15   (Units: dimensionless)
Constant
 
 CL_M
Value: 4.29   (Units: l_per_h)
Constant
 
 CL_dB
Value: 0.072   (Units: l_per_h)
Constant
 
 CL_dM
Value: 1.06   (Units: l_per_h)
Constant
 
 L_Dopa_per_kg_rat
Value: 404.0   (Units: micromole_per_kg)
Constant
 
 Benserazide_per_kg_rat
Value: 78.0   (Units: micromole_per_kg)
Constant
 
 rat_body_mass
Value: 0.25   (Units: kilogram)
Constant
 
 A_bens_tot
Value: NaN   (Units: micromole)
Constant
 
 Bens_Ro04-5127_fraction_gut
Value: 0.07
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000320

Curator's comment: (updated: 28 Mar 2011 00:19:15 BST)

Time courses for a dose of 80/20mg/kg L-Dopa/Benserazide as in figures 5 and 7 of the original article. The results were calculated using Copasi 4.6.33.

Due to problems with the use of initial assignments in Copasi, the model has to be evaluated once using either a short time-course simulation or a steady state computation to calculate and assign the correct starting values. After this, the model reproduces the correct results. Future versions of Copasi should not have this problem. The model was also tested with SBW 2.7.10, which did not exhibit this problem.

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