<?xml version="1.0"?>
<!--
This CellML file was generated on 3/11/2009 at 10:37:49 at a.m. using:
COR (0.9.31.1329)
Copyright 2002-2009 Dr Alan Garny
http://cor.physiol.ox.ac.uk/ - cor@physiol.ox.ac.uk
CellML 1.0 was used to generate this model
http://www.cellml.org/
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xml:base="" cmeta:id="grange_holford_guentert_2001" name="grange_holford_guentert_2001">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats
</title>
<author>
<firstname>Geoffrey</firstname>
<surname>Nunns</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This CellML model runs in PCenv, COR and OpenCell to recreate the published results (Figure 6). This model is simulates the administration of L-dopa only, without benserazide added. This model was created using the paper equations supplemented by suggestions made by Dr. Holford, as the original code was not available.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
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.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats, Susan Grange, Nicholas H. G. Holford, Theodor W. Guentert, 2001, <emphasis>Pharm Res.</emphasis>, volume 18, 1174-1184. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11587490 &query_hl=1&itool=pubmed_docsum">PubMed ID: 11587490 </ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
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<imagedata fileref="grange_2001a.png"/>
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<caption>Schematic diagram of the conceptual model to describe kinetics of L-dopa and 3-OMD.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
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<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">The Grange et al. 2001 pharmokinetic model of the PK interaction of L-Dopa and Benserazide in Rats</dc:title>
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<variable name="F_b_dopa" public_interface="out" units="dimensionless"/>
<variable cmeta:id="gastrointestinal_compartment_L_dopa_A_dopa_b" initial_value="101" name="A_dopa_b" public_interface="out" units="umole"/>
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<minus/>
<ci>C_Ro_peripheral</ci>
<ci>C_Ro_central</ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="peripheral_compartment_Ro">
<variable initial_value="0" name="C_Ro_peripheral" public_interface="out" units="uM"/>
<variable initial_value="3.2" name="V2_M" units="liter"/>
<variable name="time" public_interface="in" units="hour"/>
<variable name="CLd_M" public_interface="in" units="liter_per_hour"/>
<variable name="C_Ro_central" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>C_Ro_peripheral</ci>
</apply>
<apply>
<times/>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<ci>V2_M</ci>
</apply>
<ci>CLd_M</ci>
<apply>
<minus/>
<ci>C_Ro_central</ci>
<ci>C_Ro_peripheral</ci>
</apply>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_1="environment" component_2="gastrointestinal_compartment_L_dopa"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="body_compartment_L_dopa"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="body_compartment_3_OMD"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="gastrointestinal_compartment_benserazide"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="central_compartment_benserazide"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="peripheral_compartment_benserazide"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="gastrointestinal_compartment_Ro"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="central_compartment_Ro"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="peripheral_compartment_Ro"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="gastrointestinal_compartment_L_dopa" component_2="body_compartment_L_dopa"/>
<map_variables variable_1="A_dopa_b" variable_2="A_dopa_b"/>
<map_variables variable_1="F_b_dopa" variable_2="F_b_dopa"/>
<map_variables variable_1="ka_b_dopa" variable_2="ka_b_dopa"/>
</connection>
<connection>
<map_components component_1="body_compartment_L_dopa" component_2="body_compartment_3_OMD"/>
<map_variables variable_1="C_dopa_b" variable_2="C_dopa_b"/>
</connection>
<connection>
<map_components component_1="L_dopa_clearance" component_2="gastrointestinal_compartment_L_dopa"/>
<map_variables variable_1="CL_dopa_0" variable_2="CL_dopa_0"/>
</connection>
<connection>
<map_components component_1="L_dopa_clearance" component_2="body_compartment_L_dopa"/>
<map_variables variable_1="CL_dopa" variable_2="CL_dopa"/>
</connection>
<connection>
<map_components component_1="L_dopa_clearance" component_2="body_compartment_3_OMD"/>
<map_variables variable_1="CL_COMT" variable_2="CL_COMT"/>
</connection>
<connection>
<map_components component_1="L_dopa_clearance" component_2="central_compartment_Ro"/>
<map_variables variable_1="C1_M" variable_2="C_Ro_central"/>
</connection>
<connection>
<map_components component_1="gastrointestinal_compartment_benserazide" component_2="central_compartment_benserazide"/>
<map_variables variable_1="A_bens" variable_2="A_bens"/>
<map_variables variable_1="ka_Bens" variable_2="ka_Bens"/>
<map_variables variable_1="F_Bens" variable_2="F_Bens"/>
</connection>
<connection>
<map_components component_1="central_compartment_benserazide" component_2="peripheral_compartment_benserazide"/>
<map_variables variable_1="C_bens_central" variable_2="C_bens_central"/>
<map_variables variable_1="C_bens_peripheral" variable_2="C_bens_peripheral"/>
<map_variables variable_1="CLd_B" variable_2="CLd_B"/>
</connection>
<connection>
<map_components component_1="central_compartment_benserazide" component_2="benserazide_clearance"/>
<map_variables variable_1="CL_bens_total" variable_2="CL_bens_total"/>
</connection>
<connection>
<map_components component_1="gastrointestinal_compartment_Ro" component_2="central_compartment_Ro"/>
<map_variables variable_1="A_Ro" variable_2="A_Ro"/>
<map_variables variable_1="ka_M" variable_2="ka_M"/>
<map_variables variable_1="F_Ro" variable_2="F_Ro"/>
</connection>
<connection>
<map_components component_1="central_compartment_benserazide" component_2="central_compartment_Ro"/>
<map_variables variable_1="C_bens_central" variable_2="C_bens_central"/>
</connection>
<connection>
<map_components component_1="central_compartment_Ro" component_2="benserazide_clearance"/>
<map_variables variable_1="CL_Ro" variable_2="CL_Ro"/>
</connection>
<connection>
<map_components component_1="central_compartment_Ro" component_2="peripheral_compartment_Ro"/>
<map_variables variable_1="C_Ro_central" variable_2="C_Ro_central"/>
<map_variables variable_1="C_Ro_peripheral" variable_2="C_Ro_peripheral"/>
<map_variables variable_1="CLd_M" variable_2="CLd_M"/>
</connection>
</model>
