%rat parameters for use in malathion PBPK/PD model

%Parameter=value     %Description (units)-----------------------------------Reference

%blood flows
QCC=14.0;					  %Cardiac Output(L/hr/kg BW**0.75)-----------------------Brown et al 1997 
QFC=0.09;					  %Fractional Blood Flow to Fat(%QCC)---------------------Timchalk et al 2002
QLC=0.25;					  %Fractional Blood Flow to Liver(%QCC)-------------------Timchalk et al 2002
QRC=0.43;					  %Fractional Blood Flow to Richly Perfused Tissue--------Timchalk et al 2002
QBRC=0.03;           %Fractional blood flow to brain-------------------------Timchalk et al 2002
QKC=0.14;            %fraction of cardiac output to kidney-------------------Brown et al 1997

%Tissue Volumes
AGE0=1.0;           %age (days)
BW0=0.0;					  %Body Weight(kg)
VBLC=0.06;				  %Blood Volume(%BW)--------------------------------------Timchalk et al 2002
VFC=0.07;					 %Fat Volume(%BW)----------------------------------------Timchalk et al 2002
VLC=0.04;					 %Liver Volume(%BW)--------------------------------------Timchalk et al 2002
VBRC=0.012;         %Brain volume(%BW)--------------------------------------Timchalk et al 2002
VKC=0.0148;         %kidney volume (%BW)------------------------------------Brown et al 1997
VSC=0.78;           %slowly perfused tissues(%BW)---------------------------Timchalk et al 2002
VRC=0.04;           %rapidly perfused tissues(%BW)--------------------------Timchalk et al 2002
HCT=0.46;           %hematocrit
VINTC=0.022;        %intestine

%molecular weights
MWMAL=330.358;     %molecular wt of malathion (g/mol)
MWMOX=314.292;     %molecular wt of malaoxon (g/mol)


%partition coefficients (tissue:blood); from 2007 USEPA malathion lice assessment
%malathion
 PMALF = 10.;    %fat:blood
 PMALR = 5.2;    %richly perfused:blood
 PMALL = 8.0;    %liver:blood
 PMALK = 4.9;    %kidney:blood
 PMALBR = 12.8;  %brain:blood
 PMALS = 5.0;    %slowly perfused:blood
  
 %volumes of distribution for MCA+DCA compartment
 V1 = 3.6;      %MCA/DCA (L)

%malaoxon
PMOXF = 0.63;      %fat:blood
PMOXR = 1.0;       %richly perfused:blood
PMOXL = 1.17;      %liver:blood
PMOXK = 1.04;      %kidney:blood
PMOXBR = 1.45;     %brain:blood
PMOXS = 1.02;      %slowly perfused: blood


%metabolism parameters
%maximum rates of metabolism (umol/hr/kg tissue)
%malathion detoxification
VMAXMALLC = 23382;               %liver (Chambers & Meek 2017)
VMAXMALKC = 14029; %VMAXMALLC*0.6;       %kidney CaE--60% of liver, based on Talcott 1979
VMAXMALBLC = 17303; %VMAXMALLC*0.74;     %plasma (umol/hr/L serum)--74% of liver, based on Talcott 1979
VMAXMALBRC = 1169;  %VMAXMALLC*0.05;     %brain; 5% of liver

%malathion oxidation--malathion to oxon
VMAXMALMOXC = 16628.85;  %liver--CYPs; based on in vitro data--Chambers & Meek 2017

%oxon detox
VMOXDMPLC = 2000;           %liver--fit to oxon oral dose data
VMOXDMPPC = 1480; %VMOXDMPLC*0.74; %plasma--74% of liver based on Talcott
VMOXDMPBC = 100;  %VMOXDMPLC*0.05; %brain--5% of liver
VMOXDMPKC = 1200; %VMOXDMPLC*0.60; %kidney--%60 of liver based on Talcott

%affinity constants (umol/L)
%malathion detoxification
KMMALL = 0.334;            %liver--CaE--Chambers & Meek 2017
KMMALK = 0.334;            %kidney--CaE
KMMALBL = 0.334;           %plasma--CaE
KMMALBR = 0.334;           %brain--CaE

%malathion oxidation--malathion to oxon
KMMALMOX = 2730;          %liver--CYPs; based on in vitro data--Chambers & Meek 2017

%oxon detox
KMOXDMPL = 0.5;         %liver--fit to oxon oral dose data
KMOXDMPP = 0.5;         %plasma
KMOXDMPB = 0.5;         %brain
KMOXDMPK = 0.5;         %kidney
KI = 0.56;              %dissociation constant; from Krstic et al 2008 for AChE/malaoxon


%uptake parameters
%malathion
KAS=1.2;		   %transfer stomach to liver (/h)
KSI=0.2;	     %transfer stomach to intestine (/h)
KAI=0.2;       %transfer intestine to liver (/h)
FA=1;          %Fractional oral Absorption

%oxon
KASO=1.5;		 %transfer stomach to liver (/h)
KSIO=0.3;	   %transfer stomach to intestine (/h)
KAIO=0.4;     %transfer intestine to liver (/h)
FAO=1;        %Fractional oral Absorption


%elimination rate constants for metabolite compartments (/h)
KE1 = 0.2; %MCA/DCA


% Clear doses
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
DORALO=zeros(size(DORALO));
AMTODOSE=zeros(size(AMTODOSE));	% Sets all oral dose amounts to zero
AMTMDOSE=zeros(size(AMTMDOSE));	% Sets all oral dose amounts to zero
ORALMAL=0.0;
ORALMOX=0.0;


%pharmacodynamic parameters
% AChE activity (umol/hr/kg tissue) 
BACHE=4.40e5;		 %brain; Maxwell 1987,
BLACHE=2.33e4;    %plasma; Timchalk 2002
HACHE=1.02e4;     %liver; Maxwell 1987
RBCHE=3.39e4;		 %RBCs; Timchalk 2002
KACHE=5.4e3;      %kidney; Maxwell 1987

% BuChE activity (umol/hr/kg tissue) 
BBUCE=4.68e4;		%brain; Maxwell 1987
HBUCE=3.0e4;     %liver; Maxwell 1987
BLBUCE=7.85e3;	 %plasma; Timchalk 2002
LUBUCE=8.6e4;    %liver; Maxewell 1987
KBUCE=1.02e4;    %kidney; Maxwell 1987

% CaE activity (umol/hr/kg tissue) 
BRCE=2.88e5;	 %brain; Timchalk 2002
HECE=1.33e6;   %liver; de Zwart et al 2008; PND11 rats had ~70% of adult levels
PLOCE=8.4e3;   %plasma; de Zwart et al 2008; PND11 rats had ~10% of adult levels
KECE=1.79e6;   %kidney; Maxwell 1987


% Degradation of esterase (1/h)--Timchalk et al 2002
KDBBE=0.0024;              %BuChE (brain)
KDBCE=0.01;                %AChE (brain)  
KDBCR=0.000754;            %CaE (brain)
KDBLBE=0.01;               %BuChE (blood/plasma)
KDBLCE=0.003;              %AChE (blood/plasma)
KDBLCR=0.001;              %CaE (blood/plasma)
KDHBE=0.01;                %BuChE (liver)
KDHCE=0.003;		           %AChE (liver)
KDHCR=0.001;               %CaE (liver)
KDRBCE=0.003;              %AChE (RBC)
KDKBE=0.0024;              %BuChE (kidney)
KDKCE=0.01; 	             %AChE (kidney)
KDKCR=0.0033;              %CaE (kidney)

% Esterase aging rates (1/h)--chemical-specific 
% AChE aging rate from Mason et al 2000 (human RBC AChE for dimethoxy OPs)
% BuChE aging rate from Mason et al 2000 (human plasma BuChE for dimethoxy OPs)
% CaE set to zero
KABBE=0.116;              %BuChE (brain)
KABCE=0.022;              %AChE (brain)
KABCR=0.00;               %CaE (brain)
KABLBE=0.116;             %BuChE (blood/plasma)
KABLCE=0.022;             %AChE (blood/plasma)
KABLCR=0.00;              %CaE (blood/plasma)
KAHBE=0.116;              %BuChE (liver)
KAHCE=0.022;              %AChE (liver)
KAHCR=0.00;               %CaE (liver)
KARBCE=0.022;             %AChE (RBC)
KAKBE=0.116;              %BuChE (kidney)
KAKCE=0.022;              %AChE (kidney)
KAKCR=0.00;               %CaE (kidney)


% Inhibition of esterase (L/umol/h)--chemical-specific. 
% AChE from Herzsprung 1992 for bovine RBC AChE
% BuChE from Herzsprung 1992 for human plasma BuChE
% CaE from Hassan 1968 and Main & Dautermann 1968 for rat liver CaE 
KIBBE=1.26;                    %BuChE (brain)
KIBCE=16.2;                    %AChE (brain)
KIBCR=1.02;                    %CaE (brain)
KIBLBE=1.26;                   %BuChE (blood/plasma)
KIBLCE=16.2;                   %AChE (blood/plasma)
KIBLCR=1.02;                   %CaE (blood/plasma)
KIHBE=1.26;                    %BuChE (liver)
KIHCE=16.2;                    %AChE (liver)
KIHCR=1.02;                    %CaE (liver)
KIRBCE=16.2;                   %AChE (RBCs)
KIKBE=1.26;                    %BuChE (kidney)
KIKCE=16.2;                    %AChE (kidney)
KIKCR=1.02                     %CaE (kidney)

% Reactivation of esterase (1/h)--chemical specific 
% AChE reactivation rate from Mason et al 2000 (human RBC AChE for dimethoxy OPs)
% BuChE reactivation rate from Mason et al 2000 (human plasma BuChE for dimethoxy OPs)
% CaE set to same value as AChE
KRBBE=0.03;                %BuChE (brain)
KRBCE=0.018;               %AChE (brain)
KRBCR=0.018;               %CaE (brain)
KRBLBE=0.03;               %BuChE (blood/plasma)
KRBLCE=0.018;              %AChE (blood/plasma)
KRBLCR=0.018;              %CaE (blood/plasma)
KRHBE=0.03;                %BuChE (liver)
KRHCE=0.018;               %AChE (liver)
KRHCR=0.018;               %CaE (liver)
KRRBCE=0.018;              %AChE (RBCs)
KRKBE=0.03;                %BuChE (kidney)
KRKCE=0.018;               %AChE (kidney)
KRKCR=0.018;               %CaE (kidney)


% Enzyme turnover rate (substrate hydrolysis/h/active site) (Maxwell 1987)
TRCE=1.17e7;      %AChE
TRCR=1.086e5;     %CaE
TRBE=3.66e6;      %BuChE


% Timing/Integration
MAXT=0.001;       %maximum time step
MINT=1.0e-4;      %minimum time step
REPTM=1.0e6;
IALG=2;		       % Integration algorithm--Gear
POINTS=1000;


prepare @clear @all