Rendering of the source text

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<!--
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/
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	<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&amp;cmd=Retrieve&amp;dopt=AbstractPlus&amp;list_uids=11587490 &amp;query_hl=1&amp;itool=pubmed_docsum">PubMed ID: 11587490 </ulink>
				</para>
				<informalfigure float="0" id="fig_reaction_diagram">
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								<title>model diagram</title>
							</objectinfo>
							<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>
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			</sect1>
		</article>
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			<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats (L-dopa)</dc:title>
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               <apply>
                  <minus/>
                  <ci>ka_M</ci>
               </apply>
               <ci>A_Ro</ci>
            </apply>
         </apply>
      </math>
   </component>
   <component name="central_compartment_Ro">
      <variable cmeta:id="central_compartment_Ro_C_Ro_central" initial_value="0" name="C_Ro_central" public_interface="out" units="uM"/>
      <variable initial_value="0.0691" name="V1_M" units="liter"/>
      <variable initial_value="1.06" name="CLd_M" public_interface="out" units="liter_per_hour"/>
      <variable initial_value="4.29" name="CL_M" units="liter_per_hour"/>
      <variable name="time" public_interface="in" units="hour"/>
      <variable name="C_bens_central" public_interface="in" units="uM"/>
      <variable name="CL_Ro" public_interface="in" units="liter_per_hour"/>
      <variable name="A_Ro" public_interface="in" units="umole"/>
      <variable name="ka_M" public_interface="in" units="per_hour"/>
      <variable name="F_Ro" public_interface="in" units="dimensionless"/>
      <variable name="C_Ro_peripheral" 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_central</ci>
            </apply>
            <apply>
               <times/>
               <apply>
                  <divide/>
                  <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
                  <ci>V1_M</ci>
               </apply>
               <apply>
                  <plus/>
                  <apply>
                     <minus/>
                     <apply>
                        <times/>
                        <ci>ka_M</ci>
                        <ci>A_Ro</ci>
                        <ci>F_Ro</ci>
                     </apply>
                     <apply>
                        <times/>
                        <ci>CL_M</ci>
                        <ci>C_Ro_central</ci>
                     </apply>
                  </apply>
                  <apply>
                     <times/>
                     <ci>CL_Ro</ci>
                     <ci>C_bens_central</ci>
                  </apply>
                  <apply>
                     <times/>
                     <ci>CLd_M</ci>
                     <apply>
                        <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>