// Test to recreate Igari 1983 PBPK of diazepam -- 02/04/08   D Neubauer

Pbpk2CppVersion: 1.0;

Constants {
blood2PlasmaRatio: 1.037 ;
totalVolume: 70000.0 ;
volumeUnits: ml ;                 // all volumes in ml
timeUnits: sec. ;                 // all times in seconds
totalFlow:  105.5 ;               // 6330.0 / 60.0 ml/sec
startTime: 0 ;                    // seconds
stopTime:  259200 ;               // 259200= 3600 * 72 seconds (72 hours)
dTime: 1.0 ;                        // seconds
numericalIntegration: eulers ;    // eulers or rungekutta4
//numericalIntegration: rungekutta4 ;    // eulers or rungekutta4
}

Substance {
name: diazepam ;
units: ng ;
}

  
Compartment {
name: lungs ;
volume: 0.0172 ;                 // fraction of total
bloodFlow: 1.0 ;                    // fraction of CO
inputCompartment: venousBlood ;
outputCompartment: arterialBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 0.69;
massBalance: standard ;
]
}
  
Compartment {      
name: brain ;
volume: 0.0214 ;                   // fraction of total
bloodFlow: 0.120 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 0.22;
massBalance: standard ;
]
}
                   
Compartment {      
name: heart ;      
volume: 0.0043 ;                   // fraction of total
bloodFlow: 0.038 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 0.47;
massBalance: standard ;
]
}
                                                         
Compartment {      
name: liver ;
volume: 0.0214 ;                   // fraction of total
bloodFlow: 0.060 ;                    // fraction of CO
bloodFlowOutput: 0.25;               // special case: hepatic artery + gastrointestinal tract
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 1.04;
//  fu  = 0.032 ;                                     igari1983
// >>> not used!!!  fub  = fu / BLOOD2PLASMARATIO  = 3.0858e-2   ;    igari1983 p.591   fu = fub * Rb
clearance: 0.4784 ;                 // fu * (897 / 60.0)ml/sec ... from 897ml/min = 0.598 ml/min/g organ  * 1500g liver
// note: clearance is clearance of Cplasma the simulator automatically divides by partitionCoefficient to get 0.4603 ml/sec
massBalance: liverMetabolism ;
]
}
                   
Compartment {      
name: kidneys ; 
volume: 0.0043 ;                   // fraction of total
bloodFlow: 0.196 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 0.49;
massBalance: standard ;
]
}
                   
Compartment {      
name: gastrointestinalTract ; 
volume: 0.0343 ;                   // fraction of total
bloodFlow: 0.190 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: liver ;
[                    
substance: diazepam ;
partitionCoefficient: 0.40;
massBalance: standard ;
]
}
                   
Compartment {      
name: muscle ;              
volume: 0.4286 ;                   // fraction of total
bloodFlow: 0.047 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 0.29;
massBalance: standard ;
]
}
                   
Compartment {      
name: skin ;
volume: 0.1114 ;                   // fraction of total
bloodFlow: 0.308 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 0.72;
massBalance: standard ;
]
}

Compartment {      
name: adiposeTissue ;
volume: 0.1743 ;                   // fraction of total
bloodFlow: 0.041 ;                    // fraction of CO
inputCompartment: arterialBlood ;
outputCompartment: venousBlood ;
[                    
substance: diazepam ;
partitionCoefficient: 2.74;
massBalance: standard ;  
]
}
                   
Compartment {      
name: rest ;
volume: 0.1057 ;                   // fraction of total
}
                   
Compartment {      
name: arterialBlood ;
volume: 0.0257 ;                 // fraction of total
bloodFlow: 1.0 ;                    // fraction of CO
inputCompartment: lungs ;
[                    
substance: diazepam ;  
massBalance: standard ;  
]
}
                   
Compartment {      
name: venousBlood ;             
volume: 0.0514 ;                 // fraction of total
bloodFlow: 1.0 ;                    // fraction of CO
outputCompartment: lungs ;
[                    
substance: diazepam ;   
massBalance: standard ;  
]
}
                   
Dosage {
[
name: initial dose of diazepam ;
substance: diazepam;
compartment: venousBlood ;
amount: 7.0e6 ;    // (0.1 * 1.0e6 * 70.0); inject quantity in nanograms -- 0.1mg/kg, 70kg man  Igari p586 fig 5
startTime: 0 ;     // seconds
type: intravenous ;
]
}


Plotting {
plotTime: 600 ;               // 600 = 10 * 60 seconds (plot every 10 minutes)
plotTitle: PBPk of Diazepam ;
yAxis: Diazepam (ng/ml) ;
yMinimum: 1.0 ;
yMaximum: 500.0 ;  
yLog: yes;
xAxis: time (hours) ;
xScale: 3600.0 ;                    // convert seconds to hours
experimentalFile: experimental.dat ;
experimentalTitle: experimental;
substanceBlood: venousBlood.diazepam ;    // convert CbloodTotal to Cplasma
substance: adiposeTissue.diazepam ;
substance: muscle.diazepam ;
substance: brain.diazepam ;
}