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ODE.m
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function dC = ODE(c, age, sex, KEtOH,KACALD, v, q)
global kStom kSI kLI kStomSI kSILI kKid kPoop kLung aStom aLiver male bpmax iteration Solution rliv rlivALDH FBA aALDH
global molliv molc molu molbr molsw
% ETOH Compartments
% 1.adipose 2.blood 3.brain 4.SI 5.LI 6.heart 7.kidney 8.liver 9.lung
% 10.muscle 11.pancreas 12.skin 13.spleen 14.stom 15.stom_lumen
% 16.sint_lumen 17.lint_lumen
% ACALD Compartments
% 18.adipose 19.blood 20.brain 21.SI 22.LI 23.heart 24.kidney 25.liver 26.lung
% 27.muscle 28.pancreas 29.skin 30.spleen 31.stom 32.stom_lumen
% 33.sint_lumen 34.lint_lumen
r = maxrates(age, sex, c); %mM/min
% flow rate of blood into the liver: stom, s.int,l.int,pancreas,spleen,hep artery
qLiverIn=q(4)+q(5)+q(8)+q(11)+q(13)+q(14);
% concentration in vein going into liver: stom, s.int,l.int,pancreas,spleen,hep artery
cLiverInEtOH = (q(4)*c(4)/KEtOH(4) + q(5)*c(5)/KEtOH(5)+ q(8)*c(2) +q(11)*c(11)/KEtOH(11) + q(13)*c(13)/KEtOH(13) +q(14)*c(14)/KEtOH(14))/qLiverIn;
cLiverInACALD = (q(4)*c(21)/KACALD(4) + q(5)*c(22)/KACALD(5)+ q(8)*c(19) +q(11)*c(28)/KACALD(11) + q(13)*c(30)/KACALD(13) +q(14)*c(31)/KACALD(14))/qLiverIn;
% concentration in vein going back to lung with liver: adi,brain,heart,kid,liv,musc,skin
cVenEtOH = (c(1)*q(1)/KEtOH(1) + c(3)*q(3)/KEtOH(3) + c(6)*q(6)/KEtOH(6) + c(7)*q(7)/KEtOH(7) + c(8)*qLiverIn/KEtOH(8) + c(10)*q(10)/KEtOH(10) + c(12)*q(12)/KEtOH(12))/q(9);
cVenACALD = (c(18)*q(1)/KACALD(1) + c(20)*q(3)/KACALD(3) + c(23)*q(6)/KACALD(6) + c(24)*q(7)/KACALD(7) + c(25)*qLiverIn/KACALD(8) + c(27)*q(10)/KACALD(10) + c(29)*q(12)/KACALD(12))/q(9);
dC=zeros(34,1); %initialize
%% Checks if we need to run FBA
global FBAcount ModelVer tol
MMMax = r(8)*60*24; %mmol/day, liver ethanol metabolism rate
MMMaxALDH = r(25)*60*24; %mmol/day, liver acald metabolism rate
if ModelVer==2 && ((iteration == 1 || abs(aLiver*MMMax - rliv)/(aLiver*MMMax) > tol) || abs(aLiver*MMMaxALDH - rlivALDH)/(aLiver*MMMaxALDH) > tol)
%.1 --> 47 it @50min, up and down; .025 #114 @50 min, monotonic, no
%woble; 0.05 #68@50min, no wobble
FBA = 1;
FBAcount = FBAcount + 1;
fprintf('etoh: %.2f (%.2f FBA) mM/day, acald: %.2f (%.2f FBA) mM/day\n',MMMax, rliv, MMMaxALDH, rlivALDH)
fprintf('Running FBA again yields: \n')
else
FBA = 0;
end
%% Running FBA
if (ModelVer ==2 && FBA == 1)
% Ethanol transport bounds
male.ub(strmatch('Liver_ALCD2if',male.rxns))=aLiver*MMMax;
male.lb(strmatch('Liver_ALCD2if',male.rxns))=aLiver*MMMax;
%total metabolism, calculated based on liver metabolism rates assuming that the liver metabolizes 90-95% of all ethanol
totalmetMax = MMMax/0.90;
totalmetMin = MMMax/0.95;
male.ub(strmatch('Diet_EX_etoh[d]',male.rxns))=0;
male.lb(strmatch('Diet_EX_etoh[d]',male.rxns))=-100000;
male.ub(strmatch('EX_etoh[br]',male.rxns))=.005*totalmetMax; %breath
male.lb(strmatch('EX_etoh[br]',male.rxns))=.005*totalmetMax;
male.lb(strmatch('Kidney_EX_etoh(e)_[bc]',male.rxns))=-.1*totalmetMax; %have to change from 14.94 otherwise limits urine output
male.ub(strmatch('EX_etoh[u]',male.rxns))=.1*totalmetMax;
male.lb(strmatch('EX_etoh[u]',male.rxns))=.03*totalmetMin;
male.ub(strmatch('EX_etoh[sw]',male.rxns))=.1*totalmetMax;
male.lb(strmatch('EX_etoh[sw]',male.rxns))=.03*totalmetMin;
% Ethanol metabolism upper & lower bounds
male.ub(strmatch('Colon_CAT2p',male.rxns))=.02*totalmetMax;
male.lb(strmatch('Colon_CAT2p',male.rxns))=0;
male.ub(strmatch('Colon_ALCD2if',male.rxns))=0;
male.lb(strmatch('Colon_ALCD2if',male.rxns))=0;
male.ub(strmatch('Adipocytes_ALCD2if',male.rxns))=0;
male.lb(strmatch('Adipocytes_ALCD2if',male.rxns))=0;
male.ub(strmatch('Adipocytes_ALCD2yf',male.rxns))=0;
male.lb(strmatch('Adipocytes_ALCD2yf',male.rxns))=0;
% ACALD transport bounds, lots of deletions because compartment not in PBPK model
male.ub(strmatch('Gall_ALDD2y',male.rxns))=0;
male.lb(strmatch('Gall_ALDD2y',male.rxns))=0;
male.ub(strmatch('Gall_DRPA',male.rxns))=0;
male.lb(strmatch('Gall_DRPA',male.rxns))=0;
male.ub(strmatch('Gall_r0186',male.rxns))=0;
male.lb(strmatch('Gall_r0186',male.rxns))=0;
male.ub(strmatch('Gall_ALDD2x',male.rxns))=0;
male.lb(strmatch('Gall_ALDD2x',male.rxns))=0;
male.ub(strmatch('Colon_ALCD2if',male.rxns))=0;
male.lb(strmatch('Colon_ALCD2if',male.rxns))=0;
male.ub(strmatch('Retina_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Retina_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Agland_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Agland_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Thyroidgland_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Thyroidgland_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Testis_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Testis_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Prostate_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Prostate_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('CD4Tcells_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('CD4Tcells_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Nkcells_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Nkcells_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Monocyte_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Monocyte_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Platelet_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('Platelet_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('RBC_EX_acald(e)_[bc]',male.rxns))=0;
male.lb(strmatch('RBC_EX_acald(e)_[bc]',male.rxns))=0;
male.ub(strmatch('Pancreas_EX_acald[luP]_[lu]',male.rxns))=0;
male.lb(strmatch('Pancreas_EX_acald[luP]_[lu]',male.rxns))=0;
male.ub(strmatch('GI_EX_acald[lu]_[d]',male.rxns))=0;
male.lb(strmatch('GI_EX_acald[lu]_[d]',male.rxns))=0;
male.lb(strmatch('Pancreas_EX_acald[bc]_[luP]',male.rxns))=0;
male.ub(strmatch('Pancreas_EX_acald[bc]_[luP]',male.rxns))=0;
male.lb(strmatch('Liver_EX_acald[bpC]_[bpL]',male.rxns))=0;
male.ub(strmatch('Liver_ALDD2x',male.rxns))=aLiver*MMMaxALDH;
male.lb(strmatch('Liver_ALDD2x',male.rxns))=aLiver*MMMaxALDH;
% Solve FBA model
Solution=solveCobraLPCPLEX(male, 0, 0, 0, [], 0,'ILOGcomplex');
rliv=Solution.full(strmatch('Liver_ALCD2if',male.rxns)); %mmol/step
rlivALDH=Solution.full(strmatch('Liver_ALDD2x',male.rxns));
fprintf('etoh: %.2f (%.2f FBA) mM/day, acald: %.2f (%.2f FBA) mM/day\n',MMMax, rliv, MMMaxALDH, rlivALDH)
fprintf('FBA #%.0f ran at iteration #%.0f (%.2f min) \n',FBAcount, iteration, iteration/10)
fprintf('%.2f %.2f %.2f %.2f %.2f\n',molliv, molc, molu, molbr, molsw)
fprintf('--------------------------------------------\n')
end
%% PBPK solver
if (ModelVer == 1) %(Base PK model)
%EtOH
dC(1)= (q(1)/v(1)) * (c(2) - c(1)/KEtOH(1)); % 1.adipose
dC(2)= (q(9)/v(9)) * (c(9)/KEtOH(9) - c(2)); % 2.artery
dC(3)= (q(3)/v(3)) * (c(2) - c(3)/KEtOH(3)); % 3.brain
dC(4)= (q(4)/v(4)) * (c(2) - c(4)/KEtOH(4))+ kSI*c(16); % 4.s int
dC(5)= (q(5)/v(5)) * (c(2) - c(5)/KEtOH(5))+ kLI*c(17); % 5.l int
dC(6)= (q(6)/v(6)) * (c(2) - c(6)/KEtOH(6)); % 6.heart
dC(7)= (q(7)/v(7)) * (c(2) - c(7)/KEtOH(7)); % kidney
dC(8)= (qLiverIn/v(8)) * (cLiverInEtOH-c(8)/KEtOH(8)) - aLiver*r(8); % 8.liver, converted to mM/step
dC(9)= (q(9)/v(9)) * (cVenEtOH - c(9)/KEtOH(9)); % 9.lung
dC(10)= (q(10)/v(10)) * (c(2) - c(10)/KEtOH(10)); %10.muscle
dC(11)= (q(11)/v(11)) * (c(2) - c(11)/KEtOH(11)); %11.pancreas
dC(12)= (q(12)/v(12)) * (c(2) - c(12)/KEtOH(12)); %12.skin
dC(13)= (q(13)/v(13)) * (c(2) - c(13)/KEtOH(13)); %13.spleen
dC(14)= (q(14)/v(14)) * (c(2) - c(14)/KEtOH(14)) +kStom*c(15) -aStom*r(14) ;%14.stomach
dC(15)= -kStom*c(15) - kStomSI*c(15); %15.stomach_lumen
dC(16)= -kSI*c(16) - kSILI*c(16)+kStomSI*c(15); %16.sint_lumen
dC(17)= -kLI*c(17) - kPoop*c(17)+kSILI*c(16); %17.lint_lumen
%ACALD
dC(18)= (q(1)/v(1)) * (c(19) - c(18)/KACALD(1)); % 1.adipose
dC(19)= (q(9)/v(9)) * (c(26)/KACALD(9) - c(19)); % 2.artery
dC(20)= (q(3)/v(3)) * (c(19) - c(20)/KACALD(3)); % 3.brain
dC(21)= (q(4)/v(4)) * (c(19) - c(21)/KACALD(4)); % 4.s int
dC(22)= (q(5)/v(5)) * (c(19) - c(22)/KACALD(5)); % 5.l int
dC(23)= (q(6)/v(6)) * (c(19) - c(23)/KACALD(6)); % 6.heart
dC(24)= (q(7)/v(7)) * (c(19) - c(24)/KACALD(7)); % kidney
dC(25)= (qLiverIn/v(8)) * (cLiverInACALD-c(25)/KACALD(8)) + aLiver*r(8)/360 - aALDH*r(25); % 8.liver, converted to mM/step
dC(26)= (q(9)/v(9)) * (cVenACALD - c(26)/KACALD(9)); % 9.lung
dC(27)= (q(10)/v(10)) * (c(19) - c(27)/KACALD(10)); %10.muscle
dC(28)= (q(11)/v(11)) * (c(19) - c(28)/KACALD(11)); %11.pancreas
dC(29)= (q(12)/v(12)) * (c(19) - c(29)/KACALD(12)); %skin
dC(30)= (q(13)/v(13)) * (c(19) - c(30)/KACALD(13)); %13.spleen
dC(31)= (q(14)/v(14)) * (c(19) - c(31)/KACALD(14));%14.stomach
dC(32)= 0; %15.stomach_lumen
dC(33)= 0; %16.sint_lumen
dC(34)= 0; %17.lint_lumen
elseif (ModelVer == 2) %(GEM-PK model)
%EtOH
dC(1)= (q(1)/v(1)) * (c(2) - c(1)/KEtOH(1)); % 1.adipose
dC(2)= (q(9)/v(9)) * (c(9)/KEtOH(9) - c(2)); % 2.artery
dC(3)= (q(3)/v(3)) * (c(2) - c(3)/KEtOH(3)); % 3.brain
dC(4)= (q(4)/v(4)) * (c(2) - c(4)/KEtOH(4))+ kSI*c(16); % 4.s int
dC(5)= (q(5)/v(5)) * (c(2) - c(5)/KEtOH(5))+ kLI*c(17) - Solution.full(strmatch('Colon_CAT2p',male.rxns))/(1440*20);
dC(6)= (q(6)/v(6)) * (c(2) - c(6)/KEtOH(6)); % 6.heart
dC(7)= (q(7)/v(7)) * (c(2) - c(7)/KEtOH(7)) - Solution.full(strmatch('EX_etoh[u]',male.rxns))/(1440*20); % 7.kidney% 5.l int
dC(8)= (qLiverIn/v(8)) * (cLiverInEtOH-c(8)/KEtOH(8)) - aLiver*rliv/(24*60); % 8.liver, converted to mM/step
dC(9)= (q(9)/v(9)) * (cVenEtOH - c(9)/KEtOH(9)) - Solution.full(strmatch('EX_etoh[br]',male.rxns))/(1440*20); % 9.lung
dC(10)= (q(10)/v(10)) * (c(2) - c(10)/KEtOH(10)); %10.muscle
dC(11)= (q(11)/v(11)) * (c(2) - c(11)/KEtOH(11)); %11.pancreas
dC(12)= (q(12)/v(12)) * (c(2) - c(12)/KEtOH(12)) - Solution.full(strmatch('EX_etoh[sw]',male.rxns))/(1440*20); %12.skin
dC(13)= (q(13)/v(13)) * (c(2) - c(13)/KEtOH(13)); %13.spleen
dC(14)= (q(14)/v(14)) * (c(2) - c(14)/KEtOH(14)) +kStom*c(15) -aStom*r(14);%14.stomach
dC(15)= -kStom*c(15) - kStomSI*c(15); %15.stomach_lumen
dC(16)= -kSI*c(16) - kSILI*c(16)+kStomSI*c(15); %16.sint_lumen
dC(17)= -kLI*c(17) - kPoop*c(17)+kSILI*c(16); %17.lint_lumen
%ACALD
dC(18)= (q(1)/v(1)) * (c(19) - c(18)/KACALD(1)); % 1.adipose
dC(19)= (q(9)/v(9)) * (c(26)/KACALD(9) - c(19)); % 2.artery
dC(20)= (q(3)/v(3)) * (c(19) - c(20)/KACALD(3)); % 3.brain
dC(21)= (q(4)/v(4)) * (c(19) - c(21)/KACALD(4)); % 4.s int
dC(22)= (q(5)/v(5)) * (c(19) - c(22)/KACALD(5));
dC(23)= (q(6)/v(6)) * (c(19) - c(23)/KACALD(6)); % 6.heart
dC(24)= (q(7)/v(7)) * (c(19) - c(24)/KACALD(7))- Solution.full(strmatch('Colon_ALDD2xm',male.rxns))/(1440*20)-Solution.full(strmatch('Colon_ALDD2y',male.rxns))/(1440*20) - Solution.full(3896)/(1440*20); % 7.kidney% 5.l int, 3896 because strmatch no work
dC(25)= (qLiverIn/v(8)) * (cLiverInACALD-c(25)/KACALD(8)) + aLiver*rliv/(1440*360)- aALDH*rlivALDH/(1440); % 8.liver, converted to mM/step
%dC(25)= (qLiverIn/v(8)) * (cLiverInACALD-c(25)/KACALD(8)) + %aLiver*rliv/(1440*360)- aALDH*r(25); % 8.liver, converted to mM/step, works
dC(26)= (q(9)/v(9)) * (cVenACALD - c(26)/KACALD(9)); % 9.lung
dC(27)= (q(10)/v(10)) * (c(19) - c(27)/KACALD(10)); %10.muscle
dC(28)= (q(11)/v(11)) * (c(19) - c(28)/KACALD(11)); %11.pancreas
dC(29)= (q(12)/v(12)) * (c(19) - c(29)/KACALD(12)); %12.skin
dC(30)= (q(13)/v(13)) * (c(19) - c(30)/KACALD(13)); %13.spleen
dC(31)= (q(14)/v(14)) * (c(19) - c(31)/KACALD(14));%14.stomach
dC(32)= 0; %15.stomach_lumen
dC(33)= 0; %16.sint_lumen
dC(34)= 0; %17.lint_lumen
else
error ('invalid model number')
end
% molliv = molliv + aLiver*rliv/(24*60*20)*v(8);
% molc = molc + Solution.full(strmatch('Colon_CAT2p',male.rxns))/(1440*20)*v(5);
% molu = molu + Solution.full(strmatch('EX_etoh[u]',male.rxns))/(1440*20)*v(7);
% molbr = molbr + Solution.full(strmatch('EX_etoh[br]',male.rxns))/(1440*20)*v(9);
% molsw = molsw + Solution.full(strmatch('EX_etoh[sw]',male.rxns))/(1440*20)*v(12);
end