Short description
Grange2001 - L-dopa PK model

A pharmacokinetics of L-dopa in rats after administration of L-dopa alone (this model: BIOMD0000000321) or L-dopa combined with a peripheral AADC (amino-acid-decarboxylase) inhibitor (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 model has a species (A-dopa) whose initial concentration is 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.

Format
SBML (L2V3)
Related Publication
  • A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats.
  • Grange S, Holford NH, Guentert TW
  • Pharmaceutical research , 8/ 2001 , Volume 18 , pages: 1174-1184
  • PRNS Non-Clinical Drug Safety, F. Hoffmann-La Roche Ltd, Basel, Switzerland. susan.grange@roche.com
  • 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.
Contributors
Lukas Endler

Metadata information

is
BioModels Database MODEL1103250000
BioModels Database BIOMD0000000321
isDescribedBy
PubMed 11587490
hasTaxon
hasProperty
Human Disease Ontology Parkinson's disease
Curation status
Curated
  • Model originally submitted by : Lukas Endler
  • Submitted: Mar 25, 2011 11:56:49 AM
  • Last Modified: May 18, 2017 12:32:28 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: May 18, 2017 12:32:28 PM
    • Submitted by: Lukas Endler
    • With comment: Current version of Grange2001 - L Dopa PK model
  • Version: 1 public model Download this version
    • Submitted on: Mar 25, 2011 11:56:49 AM
    • Submitted by: Lukas Endler
    • With comment: Original import of Grange2001_L_Dopa_PK
Curator's comment:
(added: 28 Mar 2011, 00:21:40, updated: 28 Mar 2011, 00:21:40)
Time courses for a dose of 80 mg/kg L-Dopa as in figure 6 of the original article, has been reproduced here. 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.