clear %Start the clock tic %Experimental design Tau = 480; %Duration of experiment, minutes dt = 1; %Calculation step in minutes Time = [0:dt:Tau]; %Global follow-up in minutes %Dose Mw = 359.35; DOSE = 2000*1000000/Mw; %nmol %% Parameters Weight = 70; %Assumed, kg % Blood flows (mL/min/kg -> mL/min) SF_Q = Weight; %Multiplication factor to adjust units for blood flow QHA = 5.4*SF_Q; %Hepatic artery QGI = 15.7*SF_Q; %GI QMU = 4.6*SF_Q; %Mucosal Q1 = 36.1*SF_Q; %Blood Q2 = QMU; %GI Q3 = QHA + QGI - QMU; %Liver Q4 = 0.0714*SF_Q; %Tumor Q5 = 15.0*SF_Q; %NET Q2i = QGI - QMU; %Non-mucosal GI % Volumes (mL/kg -> mL) SF_V = Weight; %Multiplication factor to adjust units for volume V1 = 85.6*SF_V; %Blood V2 = 23.6*SF_V; %GI V3 = 21.4*SF_V; %Liver V4 = 0.286*SF_V; %Tumor V5 = 611*SF_V; %NET % Tissue:blood partition coefficients Kp21 = 0.90; %GI, Capecitabine Kp31 = 1.73; %Liver, Capecitabine Kp41 = 1; %Tumor, Capecitabine Kp51 = 0.56; %NET, Capecitabine Kp22 = 2.61; %GI, 5-DFCR Kp32 = 1.46; %Liver, 5-DFCR Kp42 = 1; %Tumor, 5-DFCR Kp52 = 0.90; %NET, 5-DFCR Kp23 = 3.11; %GI, 5-DFUR Kp33 = 1.79; %Liver, 5-DFUR Kp43 = 1; %Tumor, 5-DFUR Kp53 = 0.46; %NET, 5DFUR Kp24 = 1.71; %GI, 5-FU Kp34 = 2.78; %Liver, 5-FU Kp44 = 2; %Tumor, 5-FU Kp54 = 0.56; %NET, 5-FU % Maximum velocity of metabolism (nmol/min/g tissue -> nmol/min/mL) SF_Vmax = 1; %Multiplication factor to adjust units for Vmax, assume 1 g = 1 mL Vmax21 = 5.34*SF_Vmax; %GI, Capecitabine Vmax31 = 423*SF_Vmax; %Liver, Capecitabine Vmax41 = 20.6*SF_Vmax; %Tumor, Capecitabine Vmax22 = 32.3*SF_Vmax; %GI, 5-DFCR Vmax32 = 401*SF_Vmax; %Liver, 5-DFCR Vmax42 = 192*SF_Vmax; %Tumor, 5-DFCR Vmax23 = 53.9*SF_Vmax; %GI, 5-DFUR Vmax33 = 642*SF_Vmax; %Liver, 5-DFUR Vmax43 = 474*SF_Vmax; %Tumor, 5-DFUR Vmax24 = 1.53*SF_Vmax; %GI, 5-FU Vmax34 = 22.5*SF_Vmax; %Liver, 5-FU Vmax44 = 3.06*SF_Vmax; %Tumor, 5-FU % Affinity constant for metabolism (nmol/mL) Km21 = 3160; %GI, Capecitabine Km31 = 6430; %Liver, Capecitabine Km41 = 3170; %Tumor, Capecitabine Km22 = 6470; %GI, 5-DFCR Km32 = 5440; %Liver, 5-DFCR Km42 = 6810; %Tumor, 5-DFCR Km23 = 522; %GI, 5-DFUR Km33 = 781; %Liver, 5-DFUR Km43 = 667; %Tumor, 5-DFUR Km24 = 1.67; %GI, 5-FU Km34 = 3.17; %Liver, 5-FU Km44 = 0.377; %Tumor, 5-FU % Blood unbound fraction fB1 = 0.55; %Capecitabine fB2 = 0.95; %5-DFCR fB3 = 0.79; %5-DFUR fB4 = 1.00; %5-FU % Unbound renal clearance from blood (mL/min/kg -> mL/min) SF_CLru = Weight; %Multiplication factor to adjust units for renal clearance CLru1 = 4.72*SF_CLru; %Capecitabine CLru2 = 3.99*SF_CLru; %5-DFCR CLru3 = 3.03*SF_CLru; %5-DFUR CLru4 = 2.38*SF_CLru; %5-FU % Absorption of Capecitabine (min-1) ka = 0.0402; %Rate of absorption F = 1; %Bioavailability % Multiplication factors a1 = 80.6; a2 = 14.6; a3 = 1.30; a4 = 3.14; %% Initial conditions Blood_1 = 0; GI_1 = 0; Liver_1 = 0; Tumor_1 = 0; NET_1 = 0; Blood_2 = 0; GI_2 = 0; Liver_2 = 0; Tumor_2 = 0; NET_2 = 0; Blood_3 = 0; GI_3 = 0; Liver_3 = 0; Tumor_3 = 0; NET_3 = 0; Blood_4 = 0; GI_4 = 0; Liver_4 = 0; Tumor_4 = 0; NET_4 = 0; Absorption = DOSE; %% Assignment of parameters in a vector p = [Q1 Q2 Q3 Q4 Q5 Q2i... V1 V2 V3 V4 V5... Kp21 Kp31 Kp41 Kp51 Kp22 Kp32 Kp42 Kp52 Kp23 Kp33 Kp43 Kp53 Kp24 Kp34 Kp44 Kp54... Vmax21 Vmax31 Vmax41 Vmax22 Vmax32 Vmax42 Vmax23 Vmax33 Vmax43 Vmax24 Vmax34 Vmax44... Km21 Km31 Km41 Km22 Km32 Km42 Km23 Km33 Km43 Km24 Km34 Km44... fB1 fB2 fB3 fB4... CLru1 CLru2 CLru3 CLru4... ka F... a1 a2 a3 a4]; %% Resolution of the ODE system %Assigns the initial conditions to vector INITIALS = [Blood_1 GI_1 Liver_1 Tumor_1 NET_1 Blood_2 GI_2 Liver_2... Tumor_2 NET_2 Blood_3 GI_3 Liver_3 Tumor_3 NET_3 Blood_4 GI_4... Liver_4 Tumor_4 NET_4 Absorption]; %Resolves the system for the first dose interval options = odeset('NonNegative',[1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21]); [T,Y1]=ode15s(@model_PBPK_Tsukamoto2001,[0:dt:Tau],INITIALS,options,p); %Calculates the residual before the second daily administration Blood_1 = Y1(end,1); GI_1 = Y1(end,2); Liver_1 = Y1(end,3); Tumor_1 = Y1(end,4); NET_1 = Y1(end,5); Blood_2 = Y1(end,6); GI_2 = Y1(end,7); Liver_2 = Y1(end,8); Tumor_2 = Y1(end,9); NET_2 = Y1(end,10); Blood_3 = Y1(end,11); GI_3 = Y1(end,12); Liver_3 = Y1(end,13); Tumor_3 = Y1(end,14); NET_3 = Y1(end,15); Blood_4 = Y1(end,16); GI_4 = Y1(end,17); Liver_4 = Y1(end,18); Tumor_4 = Y1(end,19); NET_4 = Y1(end,20); Absorption = Y1(end,21); %Stores the profile Capecitabine_Blood = Y1(:,1); Capecitabine_GI = Y1(:,2); Capecitabine_Liver = Y1(:,3); Capecitabine_Tumor = Y1(:,4); Capecitabine_NET = Y1(:,5); DFCR_Blood = Y1(:,6); DFCR_GI = Y1(:,7); DFCR_Liver = Y1(:,8); DFCR_Tumor = Y1(:,9); DFCR_NET = Y1(:,10); DFUR_Blood = Y1(:,11); DFUR_GI = Y1(:,12); DFUR_Liver = Y1(:,13); DFUR_Tumor = Y1(:,14); DFUR_NET = Y1(:,15); FU_Blood = Y1(:,16); FU_GI = Y1(:,17); FU_Liver = Y1(:,18); FU_Tumor = Y1(:,19); FU_NET = Y1(:,20); %% Display of the results figure(1); clf; subplot(2,2,1) semilogy(Time,Capecitabine_Blood,'b-') hold on semilogy(Time,DFCR_Blood,'c-') semilogy(Time,DFUR_Blood,'r-') semilogy(Time,FU_Blood,'m-') hold off xlabel('Time (min)') ylabel('Concentration (nmol/mL)') title('Blood') legend('Capecitabine','5-DFCR','5-DFUR','5-FU') ylim([0.01 1000]) subplot(2,2,2) semilogy(Time,Capecitabine_Liver,'b-') hold on semilogy(Time,DFCR_Liver,'c-') semilogy(Time,DFUR_Liver,'r-') semilogy(Time,FU_Liver,'m-') hold off xlabel('Time (min)') ylabel('Concentration (nmol/mL)') title('Liver') % legend('Capecitabine','5-DFCR','5-DFUR','5-FU') ylim([0.01 1000]) subplot(2,2,3) semilogy(Time,Capecitabine_GI,'b-') hold on semilogy(Time,DFCR_GI,'c-') semilogy(Time,DFUR_GI,'r-') semilogy(Time,FU_GI,'m-') hold off xlabel('Time (min)') ylabel('Concentration (nmol/mL)') title('GI') % legend('Capecitabine','5-DFCR','5-DFUR','5-FU') ylim([0.01 1000]) subplot(2,2,4) semilogy(Time,Capecitabine_Tumor,'b-') hold on semilogy(Time,DFCR_Tumor,'c-') semilogy(Time,DFUR_Tumor,'r-') semilogy(Time,FU_Tumor,'m-') hold off xlabel('Time (min)') ylabel('Concentration (nmol/mL)') title('Tumor') % legend('Capecitabine','5-DFCR','5-DFUR','5-FU') ylim([0.01 1000]) %stop the clock and measure elapsed time toc