% Gender neutral or male specific values, except for female BTW and fat available

% Set sex=1 to access female parameters

SPECIES=1;

SEX=0;

PREG=0;

PAFC=0;

PAFO=0;

GDSTART=0;

BWST=70;

% Gompertz BWT Parameters (Luecke 2007)

B1=3.42826;B2=2.188189;B3=1.506303;B5=34.35453;B6=0.179781;B7=0.221175;

B4=2.462428;B8=-0.0911; AGE0=30;

AGE1=2.949004;AGE2=11;AGE3=21.66022;

if(SEX==1)

% set Female BWT Parameters

B1=3.4;B2=2.07402;B3=1.504154;B5=34.8806;B6=0.2120837;B7=0.443786;

B4=2.672665;B8=0.31127;

AGE1=2.949004;AGE2=11;AGE3=21.86533;

end

% Dynamic organ volumes

% VBC Parameters (Refit Valentine 2002 & Young 2009)

VB6=0;VB5=0;VB4=5.132e-22;VB3=-2.463e-16;VB2=4.354e-11;

VB1=-3.465e-6;VB0=1.216e-1;

% VHC (Refit Valentine 2002 & Young 2009)

VH4=1.701E-22;VH3=-7.393E-17;VH2=1.082E-11;VH1=-6.789E-7;VH0=3.917E-2;

% VBL (Young 2009)

VBL2=6.54E-13;VBL1=-3.50E-7;VBL0=8.97E-2;

% VFC (Refit, JNS w/ Valentin 2002 & Lafortuna 2005)

VF6=-2.036e-30;VF5=1.203e-24;VF4=-2.718e-19;VF3=2.892e-14;VF2=-1.422e-09;

VF1=2.803e-05;VF0=3.484e-02;

if(SEX==1)

% set Female VFC

VF6=-1.273e-30;VF5=7.249e-25;VF4=-1.558e-19;VF3=1.540e-14;VF2=-6.787e-10;

VF1=1.401e-05;VF0=9.217e-02;

end

% VAC (Fit, JNS w/ Valentin 2002 & Lafortuna 2005 fat/.8)

VA6=-2.353e-30;VA5=1.387e-24;VA4=-3.116e-19;VA3=3.268e-14;VA2=-1.542e-9;VA1=2.617e-05;

VA0=2.044e-01;

% VLC (Young 2009)

VL2=0;VL1=-4.55e-8;VL0=1.86e-2;

% VKC (Young 2009)

VK2=3.33e-13;VK1=-6.69e-8;VK0=7.26e-3;

% VSPC (Young 2009)

VSP2=0;VSP1=-5.57e-9;VSP0=3.12e-3;

% VGIC (Brown 1997, sum of stom and both intestines)

VGI3=0;VGI2=0;VGI1=0;VGI0=0.0165;

% VMC (Refit, JNS w/ Valentin 2002 & Janssen 2000)

VM4=-5.061e-21;VM3=2.052e-15;VM2=-2.865e-10;VM1=1.436e-5;VM0=1.268e-1;

% VSKC (Young 2009)

VSK5=-1.1e-27;VSK4=8.62e-22;VSK3=-2.58e-16;VSK2=3.68e-11;

VSK1=-2.56e-6;VSK0=1.03e-1;

% Constant organ volumes

VBMC=0.021;% Brown 1997 (red only, yellow is in adipose)

VDC=0.0003;

VPC=0.00148; % Young 2009, Brown 1997

VINTC=0.0091;% Just small intestine (Brown 1997)

VFETC=0,VPLAC=0,VFI=0,VFINIT=0;
% Clear doses

DT(200), DORAL(200), DSC(200), DORALO(200), AMTCDOSE(200), AMTODOSE(200);

DT=ones(size(DT))*1E6; % Sets all oral dose times to a long time

DORAL=zeros(size(DORAL));% Sets all oral dose amounts to zero

DSC=zeros(size(DSC));% Sets all SC dose amounts to zero

DORALO=zeros(size(DORALO));

AMTODOSE=zeros(size(AMTODOSE));% Sets all oral dose amounts to zero

AMTCDOSE=zeros(size(AMTCDOSE));% Sets all oral dose amounts to zero

CONCPPM=0.0;

CONCMGM=0.0;

CONCMG=0.0;

N=1;

VCHA=5e10;

DERM=0.0;

ORALC=0.0;

ORALO=0.0;

ORALP=0.0;

CONCL=0.0;

DERM=0;

IV=0.0;% IV dose (ug/kg)

IVS=0.0;% IV start time (h)

IVE=0.1;% IV end time (h)

SCDC=0.0;% SC dose

FEED=0.0;% Feed dose (ug/kg feed)

FEEDR=0.0;% Feed rate (kg/h)

FEEDT=0.0;% Feed time

SLORAL=0.0;% Repeated oral gavage dose

SA=100;% Surface area exposed dermally (SQ CM)

VLIQ=1.0; % Volume of dose applied to skin (L)

%TSA=20466;% Total surface area (SQ CM), human value!

TCHNG=5e55;% Time to stop dermal exposure

%TSTOP=1

% Transfer Rates

KAS=0.;% CPF stomach -> liver this is for rat only, set to 0 for human

KSI=0.31;% CPF stomach -> intestine, optimized with Nolan 1984 CBLP and AE

KAI=3.1; % CPF intestine -> liver, optimized with Nolan 1984 CBLP and AE

KIHP=8.7;% TCPy intestine -> liver

KOS=2;% CPF-oxon intestine -> liver

KOSI=1.5; %CPF-oxon from an oral dose ->intestine (OPTIMIZED IN RATS)

KSC=0.0;% Central SC compart -> blood

KSP=0.0;% Central SC -> peripheral SC

KPS=0.0;% Peripheral SC -> central SC

KPL=5.5e-5; %optimized against Nolan data

FA=1; % Fractional oral Absorption

FAD=1; %FRACTIONAL DERMAL ABSORPTION

% Small intestine metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM)

VINTTC= 53;%parallogram approach from measured in rat liver->Intestine(Poet et al., 

2003)to human

KMINTC=21; % - scaling hepatic by protein content gives 53*0.39=21

VINTOC=28 ; %parallogram approach from measured in rat liver->Intestine(Poet et al., 

2003)to human

KMINTO=33.2;% scaling hepatic by protein content = 85*0.39=33.2

VINTOXC=82 ; %parallogram approach from measured in rat liver->Intestine(Poet et al., 

2003)to human

KMINTOX=192;% scaling hepatic by protein content 492*0.39=192

% Hepatic metabolic constants, Vmaxc (umol/hr/g tissue), Km (uM)

VMHCP=1.36e3;% CPF -> TCP, median from Smith 2010 B

KMHCP=21; % Smith 2010 median; 53- scaling hepatic by protein content gives 53*0.39=21

VMHHCO=6.30E2;% CPF -> CFP-oxon, Smith 2010 median

KMHHCO=33.2; % Smith 2010 median; 85 scaling hepatic by protein content = 85*0.39=33.2
VML=1.29e+05;% CPF-oxon -> TCP, Smith 2010B median

KMLST=192; % Smith 2010 median; 491.8 - scaling hepatic by protein content 492*0.39=192

% Plasma metabolic constants, Vmaxc (umol/hr/L plasma), Km (uM)

VMBL1=432000;VMBL2=3.052;VMBL3=3.900;% CPF-oxon -> TCP, logistic fit to Smith 2010 B

KMBLST=192.0;% Smith 2010 B: 192.0 med, 203.2 mean

% Brain metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM)

VMCBCO=12.6;% CPF -> CPF-oxon, 0.149 Extrap from Chambers 1989, 0.91 Extrap from 

Layshock 2009 unpub, estimated at 2% hepatic

KMBCO=33.2;% Same as liver

VMCBCP=27.2;% CPF -> TCPy, Extrap from Layshock 2009 unpub

KMBCP=21;% Same as liver

KMBCPT=192;%Brain oxon ->TCPy

VMBCPTC=1.94e4; %Brain oxon ->TCPy

%lung

KMOLU=33.2;%liver

KMTLU=21;

VMAXTLUC=1.36e3;% LUNG CPF->TCP

VMAXOLUC=6.3e2; % LUNG CPF->OXON

VMAXPLUC=27.2 ; %2% of liver

KMPLUC= 192;

KMUC=0.02; %OPTIMIZED IN RATS (FROM Hotchkiss inhalation report)

FRACIN=0.046; %MPPD MODEL PREDICTed REACHING DEEP LUNG (0.233 for the mid dose per J. 

Hotchkiss), 20% of that optimize

% diaphragm metabolism parameters, Vmaxc (umol/hr/g tissue), Km (uM)copied from brain

VMCDPCO=12.6;% CPF -> CPF-oxon, 2% OF HEPATIC

KMDPCO=33.2;% Same as intestine

VMCDPCP=27.2;% CPF -> CPF-oxon, 2% OF HEPATIC

KMDPCP=21;% Same as intestine

%DERMAL

VMCDERMCO=12.6;% CPF -> CPF-oxon, 2% OF HEPATIC

KMDERMCO=33.2;% same as hepatic

VMCDERMCP=27.2;% CPF -> CPF-oxon, 2% OF HEPATIC. Extrap from Layshock 2009 unpub

KMDERMCP=21;% Same as hepatic

KMDERMEST=19;% Km CPF-oxon -> TCPy (umol/L), same as hepatic

VMDERMESTC=1.94e4;% dermal Vmaxc CPF-oxon -> TCPy (umol/hr/kg tissue) - 10-15% of liver 

this is, Jewell et al Tox Let 07- general skin esterase 10% of liver in humans - Beydon 

et al Tox In vitro, 2010

KDIS=0.;

% TCP Excretion

KE=0.024; % Optimized with Nolan 1984 IBLE1 and AE

% Protein Binding

FBC=0.99;% 0.99 Lowe 2009

FBO=0.99;% 0.99 Lowe 2009

FUBO=0.01;

FUBC=0.01;

% Timing/Integration

MAXT=0.001;

MINT=1.0e-006;

REPTM=1.0E+6;

%POINTS=1000;

% Molecular Wts (g/mol)

MWC=350.6;

MWO=334.5;

MWP=198.0;
% HCT

HCTN=0.45; % 0.43 women, 0.47 men (Bresarb 1998)

% Partitioning Coef. (Lowe 2009)

% CPF

PFCN=250.0;% Fat/blood

PHC=12.8; % Liver/blood

PRC=16.5; % Richly perfused/blood

PSC=3.85; % Slowly perfused/blood

PDC=3.85; % Diaphram/blood

PBC=16.5; % Brain/blood

PSK=6.8;% Skin/Blood

PSKL=200; %liquid/skin - actually a factor of both Q and partitioning - optimized

PBL=1.0;% Blood/blood

PLU=16.5;% Lung/blood = rapid

PLAIR=7.6e5;%BARTELS 'generic' paper, calculated Poulen/Theil (25deg C)

PPLA=3.85; %PLACENTA=SLOW

% CPF-oxon

PFON=75.0;% Fat/blood

PHO=4.5; % Liver/blood

PRO=5.6; % Richly perfused/blood

PSO=1.8; % Slowly perfused/blood

PDO=1.8; % Diaphram/blood

PBO=5.6;% Brain/blood

PBLO=1;% Blood/blood

PLUO=5.6;% Lung/blood = rapid

PLAIRO=7.6e5;%BARTELS 'generic' paper, calculated Poulen/Theil (25deg C), ASSUME =CPF

PSKO=125;%liquid/skin - actually a factor of both Q and partitioning - =CPF

PPLAO=1.8; %PLACENTA=SLOW

% BuChE activity (umol/hr/kg tissue) (Maxwell 1987)

BBUCE=4.68e4;% 4.68E4 Maxwell 1987

DBUCE=2.64e4;

HBUCE=3.0e4;

BLBUCE=2.63e5;% 2.63E5 Sidell 1975

LUBUCE=8.6e4; %Maxwell, 87

% CaE activity (umol/hr/kg tissue) (Maxwell 1987)

BRCE=2.88e5;% based on Hojring 1976 scaled by hepatic

DACE=3.18e5;

HECE=1.27e6; % based on Pope 2005, timchalk 02/Maxwell

PLOCE=1e-99;% 0 Li 2005

LUECE=1.4e6; %Maxwell, 87

% AChE activity (umol/hr/kg tissue) (Maxwell 1987)

BACHE=4.40e5;% 4.40E5 Maxwell 1987,

BLACHE=1e-99; % 1248 Li 2005 & Brimijoin 1988

DACHE=7.74e4;

HACHE=1.02e4;

RBCHE=4.27e5;% 4.27E5 Albers 2009,

LUACHE=2.28e4 ;%Maxwell, '87 -

% Esterase aging rates (1/h)

KABBE=0.0113;

KABCE=0.0113;

KABCR=0.0113;

KABLBE=0.0113;

KABLCE=0.0113;

KABLCR=0.0113;

KADBE=0.0113;

KADCE=0.0113;

KADCR=0.0113;

KAHBE=0.0113;

KAHCE=0.0113;
KAHCR=0.0113;

KARBCE=0.0113;

KALUCR=0.0113;

% Degradation of esterase (1/h)

KDBBE=0.0024;

KDBCE= 0.01;

KDBCR=0.000754;

KDBLBE=0.0024;

KDBLCE=0.01;

KDBLCR=0.0033;

KDDBE=0.0024;

KDDCE=0.01;

KDDCR=0.001;

KDHBE=0.0024;

KDHCE=0.01;

KDHCR=0.001;

KDRBCE=0.01;

KDLUCE=0.01;

% Inhibition of esterase (L/umol/h)

KIBBE=2000;

KIBCE=220;

KIBCR=20;

KIBLBE=2000;

KIBLCE=220;

KIBLCR=20;

KIDBE=2000;

KIDCE=220;

KIDCR=20;

KIHBE=2000;

KIHCE=220;

KIHCR=20;

KIRBCE=100;

KILUBE=2000;

KILUCE=220;

KILUCR=20;

% Reactivation of esterase (1/h)

KRBBE=0.0014;

KRBCE=0.014;

KRBCR=0.014;

KRBLBE=0.0014;

KRBLCE=0.014;

KRBLCR=0.014;

KRDBE=0.0014;

KRDCE=0.014;

KRDCR=0.014;

KRHBE=0.0014;

KRHCE=0.014;

KRHCR=0.014;

KRRBCE=0.014;

KRLUBE=0.0014;

KRLUCE0=0.014;

KRLUCR=0.014;

% Enzyme turnover rate (substrate hydrolysis/h/active site) (Maxwell 1987)

TRCE=1.17e7;

TRCR=1.086e5;

TRBE=3.66e6;

% Blood flows (L/h/kg tissue)

QBC=30.6;% Price 2003

QDC=85.2;% Luecke 2007

QFC=1.45;% Luecke 2007, Cowles 1971, Price 2003
QHC=50.4;% Hepatic art, Price 2003

QSC=1.8;% Bone marrow, Price 2003

QRC=61.8;% Adreanal/spleen mean, Luecke 2007

SAF=1e-99;

QPC=27.75;

QSKC=12; %Approx skin blood flow to skin /kg of tissue

% turn off all model variability terms

VMLV=0.0;

VMBLV=0.0;

VMHCPV=0.0;

VMHHCOV=0.0;

VINTTV=0.0;

VINTOV=0.0;

KIRBCEV=0.0;

QHCV=0.0;

HCTV=0.0;

HECEV=0.0;

KRHCRV=0.0;

KRRBCEV=0.0;

VHCV=0.0;

KSIV=0.0;

KDRBCEV=0;

FATVAR=0.;

VBLV=0.0;

VHCV=0.0;

KUNCERT=0.0;

start @nocallback