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demin1

The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000490) Biomodels notes: Figure 2 of the reference publication has been reproduced here. To simulate the curves of Figure 2, (i) set a=1 ("1" corresponds to multiple dose administration, "0" corresponds to single dose administration), (ii) set DOSE_zf to 400 or 600 (this corresponds to the dosage of Zileuton in mg), and (iii) set DOSE_ml to 10 or 50 (this corresponds to the dosage of Montelukast in mg). The model was simulated using Copasi v4.10 (Build 55) and the plots were generated using Gnuplot. The Copasi file corresponding to each of these four conditions (i.e.,DOSE_zf=400,600mg and DOSE_ml=10,50mg) that can be used to generate the plots, can be downloaded (see below). JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.

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Manuscript information

Systems pharmacology models can be used to understand complex pharmacokinetic-pharmacodynamic behavior: an example using 5-lipoxygenase inhibitors.

  • T Karelina
  • D Svetlichniy
  • E Metelkin
  • G Speshilov
  • O Demin
  • D Fairman
  • Piet H van der Graaf
  • BM Agoram
CPT Pharmacometrics Syst Pharmacol 2013; 2 :
Abstract
Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO enzyme, leukotriene signaling and bronchodilation, and the PK of zileuton. The model provided a plausible explanation for the two-phase bronchodilatory effect of zileuton-the short-term bronchodilation was due to leukotriene inhibition and the long-term bronchodilation was due to inflammatory cell infiltration blockade. The model also indicated that the theoretical maximum bronchodilation of both 5LO inhibition and leukotriene receptor blockade is likely similar. QSP modeling provided interesting insights into the effects of leukotriene modulation.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e74; doi:10.1038/psp.2013.49; advance online publication 11 September 2013.

Unit definitions 0

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Name Definition

Compartments 16

Id Name Spatial dimensions Size
Default — 3.0 1.0
V_AW — 3.0 0.209999993443489
V_B — 3.0 2.80999994277954
V_BM — 3.0 0.824999988079071
Vd_AW_Hn — 3.0 5640.0
Vd_AW_LTC — 3.0 1.53999996185303
Vd_AW_LTD — 3.0 1.53999996185303
Vd_AW_LTE — 3.0 1.53999996185303
Vd_AW_ZF — 3.0 3.25999999046326
Vd_Hn — 3.0 78100.0
Vd_IL5 — 3.0 10.1999998092651
Vd_LTC — 3.0 9.47999954223633
Vd_LTD — 3.0 9.47999954223633
Vd_LTE — 3.0 9.47999954223633
Vd_ML — 3.0 10.0
Vd_ZF — 3.0 9.44999980926514

Species 33

Id Name Initial quantity Compartment Fixed
AA_aw AA_aw 0.1304887 Default ✘
AA_b AA_b 0.2890944 Default ✘
EO_a_aw EO_a_aw 0.001358713 V_AW ✘
EO_a_b EO_a_b 0.0005383185 V_B ✘
EO_aw EO_aw 0.000001176558 V_AW ✘
EO_b EO_b 0.000000468114 V_B ✘
EO_bm EO_bm 0.000001637391 V_BM ✘
EO_i_aw EO_i_aw 0.0000001358698 V_AW ✘
EO_i_b EO_i_b 0.00000005479176 V_B ✘
HETE_aw HETE_aw 1.960926 Default ✘
HETE_b HETE_b 5.037703 Default ✘
HPETE_aw HPETE_aw 1.780604 Default ✘
HPETE_b HPETE_b 0.2965837 Default ✘
Hn_aw Hn_aw 14162.15 Vd_AW_Hn ✘
Hn_b Hn_b 14995.88 Vd_Hn ✘
IL_aw IL_aw 0.6627439 V_AW ✘
IL_b IL_b 0.5994857 Vd_IL5 ✘
IL_bm IL_bm 0.4023394 V_BM ✘
LTA4_aw LTA4_aw 41.69257 Default ✘
LTA4_b LTA4_b 1.081167 Default ✘
LTC4_aw LTC4_aw 6.806687 Default ✘
LTC4_aw_out LTC4_aw_out 359.9744 Vd_AW_LTC ✘
LTC4_b LTC4_b 0.8869873 Default ✘
LTC4_b_out LTC4_b_out 2168.571 Vd_LTC ✘
LTD4_aw LTD4_aw 205.7602 Vd_AW_LTD ✘
LTD4_b LTD4_b 1308.488 Vd_LTD ✘
LTE4_aw LTE4_aw 322.6366 Vd_AW_LTE ✘
LTE4_b LTE4_b 2053.137 Vd_LTE ✘
ML_blood ML_blood 0.0 Vd_ML ✘
ML_intes ML_intes 0.0 Default ✘
ZF_airways ZF_airways 0.0 Vd_AW_ZF ✘
ZF_blood ZF_blood 0.0 Vd_ZF ✘
ZF_intes ZF_intes 0.0 Default ✘

Initial assignments 0

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Definition
Reactions 66
Id Name Objective coefficient Reaction Equation and Kinetic Law Flux bounds
v1 v1 ∅ > AA_b

Default * (Vmax_PLA2 * PLA2_Ca * PL / (Km_PLA2_APC + PL) - V_CoA * AA_b / (Km_CoA_AA + AA_b))
v10in v10in LTC4_b > ∅

Default * Kd50 * LTC4_b
v10out v10out ∅ > LTC4_b_out

Default * Kd50 * LTC4_b * V_LTC_CB * pow(1.000000e+01, 6.000000e+00)
v11 v11 LTC4_b_out > LTD4_b

Vd_LTC * k_ggt * fup_LT * LTC4_b_out
v12 v12 LTD4_b > LTE4_b

Vd_LTD * k_dp * fup_LT * LTD4_b
v13 v13 LTC4_b_out > ∅

Vd_LTC * k_ltc_ltd_el * fup_LT * LTC4_b_out
v14 v14 LTD4_b > ∅

Vd_LTD * k_ltc_ltd_el * fup_LT * LTD4_b
v15 v15 LTE4_b > ∅

Vd_LTE * (k_lte_el + k_acet) * fup_LT * LTE4_b
v16 v16 EO_b > EO_i_b

ca * V_B * (ka * EO_b * pow(OL_b, h_act) / (pow(EC50_act, h_act) + pow(OL_b, h_act)))
v17 v17 EO_i_b > EO_a_b

ca * V_B * k_EO_m * EO_i_b
v18 v18 EO_a_b > EO_b

ca * V_B * kia * EO_a_b
v19 v19 EO_b > ∅

V_B * k_EO_d * EO_b
v2 v2 AA_b > ∅

Default * (k_lo * AA_b * FLO3t_b / K_AA)
v20 v20 EO_a_b > ∅

V_B * k_EO_a_d * EO_a_b
v21 v21 EO_i_b > EO_i_aw

V_B * (k_EO_t_baw * EO_i_b * pow(Rec_occup_migr, h_migr) / (pow(EC50_migr, h_migr) + pow(Rec_occup_migr, h_migr)))
v22 v22 EO_a_b > EO_a_aw

V_B * (k_EO_t_baw * EO_a_b * pow(Rec_occup_migr, h_migr) / (pow(EC50_migr, h_migr) + pow(Rec_occup_migr, h_migr)))
v23 v23 EO_b > EO_aw

V_B * (k_EO_t_baw * EO_b * pow(Rec_occup_migr, h_migr) / (pow(EC50_migr, h_migr) + pow(Rec_occup_migr, h_migr)))
v24 v24 ∅ > Hn_b

V_B * k_Hn_p * (EO_b + EO_i_b + EO_a_b)
v25 v25 Hn_b > ∅

Vd_Hn * k_Hn_d * fup_Hn * Hn_b
v26 v26 ∅ > IL_b

V_B * k_IL_p * EO_a_b
v27 v27 IL_b > ∅

Vd_IL5 * k_IL_d * IL_b
v28 v28 IL_b > IL_bm

k_IL_t_bbm * (IL_b - IL_bm) - J_BM_lymfl * IL_bm
v29 v29 ∅ > EO_bm

V_BM * (k1 * pow(IL_bm, h_matur) / (pow(Km_1, h_matur) + pow(IL_bm, h_matur)) + k1_min)
v3 v3 ∅ > HPETE_b

Default * (k_3 * FLO5HP_b - k3 * FLO3t_b * HPETE_b) * (1.000000e+00 + AA_b / Ki_AA)
v30 v30 EO_bm > EO_b

ca * V_BM * k_EO_t_bmb * EO_bm
v31 v31 ∅ > AA_aw

Default * (Vmax_PLA2 * PLA2_Ca * PL / (Km_PLA2_APC + PL) - V_CoA * AA_aw / (Km_CoA_AA + AA_aw))
v32 v32 AA_aw > ∅

Default * (k_lo * AA_aw * FLO3t_aw / K_AA)
v33 v33 ∅ > HPETE_aw

Default * (k_3 * FLO5HP_aw - k3 * FLO3t_aw * HPETE_aw) * (1.000000e+00 + AA_aw / Ki_AA)
v34 v34 HPETE_aw > HETE_aw

Default * r1 * (HPETE_aw * FLO2_aw - HETE_aw * FLO3_aw / Ke_ox)
v35 v35 HPETE_aw > HETE_aw

Default * (GPx * B_aw / A_aw)
v36 v36 ∅ > LTA4_aw

Default * k_lta_syn * FLO5HP_aw
v37 v37 LTA4_aw > LTC4_aw

Default * (nom_LTCs_aw / den_LTCs_aw)
v38 v38 HETE_aw > ∅

Default * (HEDH5 * B_hedh_aw / A_hedh_aw)
v39 v39 LTA4_aw > ∅

Default * Kd12 * LTA4_aw
v4 v4 HPETE_b > HETE_b

Default * r1 * (HPETE_b * FLO2_b - HETE_b * FLO3_b / Ke_ox)
v40in v40in LTC4_aw > ∅

Default * Kd50 * LTC4_aw
v40out v40out ∅ > LTC4_aw_out

Default * Kd50 * LTC4_aw * V_LTC_CAW * pow(1.000000e+01, 6.000000e+00)
v41 v41 LTC4_aw_out > LTD4_aw

Vd_AW_LTC * k_ggt * LTC4_aw_out
v42 v42 LTD4_aw > LTE4_aw

Vd_AW_LTD * k_dp * LTD4_aw
v43 v43 LTE4_aw > LTE4_b

Q_AW_blf * R_LTE_B * (LTE4_aw * R_LTE_AW / Kp_LTE_AW - LTE4_b)
v44 v44 LTD4_aw > LTD4_b

Q_AW_blf * R_LTD_B * (LTD4_aw * R_LTD_AW / Kp_LTD_AW - LTD4_b)
v45 v45 LTC4_aw_out > LTC4_b_out

Q_AW_blf * R_LTC_B * (LTC4_aw_out * R_LTC_AW / Kp_LTC_AW - LTC4_b_out)
v46 v46 EO_aw > EO_i_aw

ca * V_AW * (ka * EO_aw * pow(OL_aw, h_act) / (pow(EC50_act, h_act) + pow(OL_aw, h_act)))
v47 v47 EO_i_aw > EO_a_aw

ca * V_AW * k_EO_m * EO_i_aw
v48 v48 EO_a_aw > EO_aw

ca * V_AW * kia * EO_a_aw
v49 v49 EO_aw > ∅

V_AW * k_EO_d * EO_aw
v5 v5 HPETE_b > HETE_b

Default * (GPx * B_b / A_b)
v50 v50 EO_a_aw > ∅

V_AW * k_EO_a_d * EO_a_aw
v51 v51 ∅ > Hn_aw

V_AW * k_Hn_p * (EO_a_aw + EO_i_aw + EO_aw)
v52 v52 Hn_aw > Hn_b

Q_AW_blf * R_Hn_B * (Hn_aw * R_Hn_AW / Kp_Hn_AW - Hn_b)
v53 v53 ∅ > IL_aw

V_AW * k_IL_p * EO_a_aw
v54 v54 IL_aw > IL_b

k_IL_t_awb * (IL_aw - IL_b) + J_AW_lymfl * IL_aw
v55 v55 LTE4_aw > ∅

Vd_AW_LTE * (k_lte_el + k_acet) * LTE4_aw
v56 v56 LTD4_aw > ∅

Vd_AW_LTD * k_ltc_ltd_el * LTD4_aw
v57 v57 LTC4_aw_out > ∅

Vd_AW_LTC * k_ltc_ltd_el * LTC4_aw_out
v58 v58 IL_aw > ∅

V_AW * k_IL_d * IL_aw
v59 v59 Hn_aw > ∅

Vd_AW_Hn * k_Hn_d * Hn_aw
v6 v6 ∅ > LTA4_b

Default * k_lta_syn * FLO5HP_b
v60 v60 ZF_intes > ZF_blood

Default * k_abs_zf * (ZF_intes + oral * F_zf * (a * ft_zf + (1.000000e+00 - a)) * DOSE_zf * 1.000000e+03 / M_ZF)
v61 v61 ZF_blood > ZF_airways

Q_AW_blf * R_ZF_B * (ZF_blood - ZF_airways * R_ZF_AW / Kp_ZF_AW)
v62 v62 ZF_blood > ∅

Vd_ZF * k_elim_zf * ZF_blood
v63 v63 ML_intes > ML_blood

Default * k_abs_ml * (ML_intes + oral * F_ml * (a * ft_ml + (1.000000e+00 - a)) * DOSE_ml * 1.000000e+09 / M_ML)
v64 v64 ML_blood > ∅

Vd_ML * k_elim_ml * ML_blood
v7 v7 LTA4_b > LTC4_b

Default * (nom_LTCs_b / den_LTCs_b)
v8 v8 HETE_b > ∅

Default * (HEDH5 * B_hedh_b / A_hedh_b)
v9 v9 LTA4_b > ∅

Default * Kd12 * LTA4_b

Parameters 0   263

Global parameters

Id Value
A_aw 0.0
A_b 0.0
A_hedh_aw 0.0
A_hedh_b 0.0
B_aw 0.0
B_b 0.0
B_hedh_aw 0.0
B_hedh_b 0.0
C_aw 0.0
C_b 0.0
C_hedh_aw 0.0
C_hedh_b 0.0
Ca 1.0
Ca_FEV 0.0
Ca_FEV_LTR1 0.0
Ca_FEV_LTR2 0.0
Ca_FEV_ex 10000.0
Cao_FEV 10000.0
DFLOa_aw 0.0
DFLOa_b 0.0
DOSE_ml 0.0
DOSE_zf 0.0
EC50_ML_FEV 500.0
EC50_act 0.75
EC50_migr 0.115
EO_aw_tot 0.0
EO_b_tot 0.0
EO_b_tot_per_ss 0.0
Et_LTCs 1.0
FEV1 0.0
FEV1_percent 0.0
FLO2_aw 0.0
FLO2_b 0.0
FLO2t_aw 0.0
FLO2t_b 0.0
FLO3_aw 0.0
FLO3_b 0.0
FLO3t_aw 0.0
FLO3t_b 0.0
FLO5HP_aw 0.0
FLO5HP_b 0.0
FLOa 1.5
F_ml 0.660688
F_zf 0.082
GPx 1.6
GSH_aw 1000.0
GSH_b 5000.0
GSSG_aw 0.0
GSSG_b 0.0
GS_pool_aw 10000.0
GS_pool_b 10000.0
HEDH5 0.5
Hn_aw_perc 0.0
J_AW_lymfl 0.00115
J_BM_lymfl 0.00049
K_AA 10.74959
K_AA_HETE 0.0
K_Ca2 14.36738
K_Ca3 7116.527
K_Ca_FEV 150000.0
K_GSH 744.9176
K_LTA 1.75951
K_LTA_GSH 1696.6
K_LTC 0.1951215
K_PLA2_Ca 0.1
Kd12 0.007
Kd50 0.43
KdZ 20.0
Kd_Hn_FEV 6300000.0
Kd_IL_migr 50.0
Kd_LT 1000.0
Kd_LTE_migr 50000.0
Kd_LTR1_FEV 1000.0
Kd_LTR2_FEV 10000.0
Kd_LT_2 10000.0
Kd_gpx_GSSG 0.07154222
Kd_gpx_HETE5 6.043446
Kd_hedh_HETE5 0.331696
Kd_hedh_NADP 2.895899
Kd_hedh_NADPH 2.685581
Kd_hedh_oxoETE5 1.667019
Ke_ox 99.99979
Ke_red 0.0000005761955
Ki_AA 551.8748
Ki_AA_AA 0.0
Ki_HETE 0.5408177
Ki_HPETE_AA 0.0
Ki_ML_EOa 500.0
Km_1 2.0
Km_CoA_AA 0.005
Km_PLA2_APC 20.0
Km_gpx_GSH 600.0
Km_gpx_HPETE5 5.974381
Kp_Hn_AW 3950.0
Kp_LTC_AW 0.22
Kp_LTD_AW 0.22
Kp_LTE_AW 0.22
Kp_ZF_AW 0.204
Kp_ZF_IW 0.631
LOH_aw 0.0
LOH_b 0.0
LOOH_aw 20.0
LOOH_b 1.0
LTC4_b_pM 0.0
LTD4_aw_pers 0.0
LTD4_b_free 0.0
LTs_aw_pg 0.0
MAX_FEV 4.94
ML_airways 0.0
ML_airways_conc 0.0
ML_blood_conc 0.0
ML_ex 0.0
ML_uM 0.0
M_Hn 111.2
M_IL5 45000.0
M_LTC 625.8
M_LTD 496.7
M_LTE 439.6
M_ML 586.18
M_ZF 236.0
NADPH_aw 0.0
NADPH_b 0.0
NADP_aw 2900.0
NADP_b 2000.0
NP_pool_aw 3000.0
NP_pool_b 3000.0
N_A_pmole 602000000000.0
N_EO 0.0
N_EO_a 0.0
N_EO_a_aw 0.0
N_EO_a_b 0.0
N_EO_aw 0.0
N_EO_aw_perc 0.0
N_EO_aw_tot 0.0
N_EO_aw_tot_perc 0.0
N_EO_b 0.0
N_EO_b_tot 0.0
N_EO_b_tot_perc 0.0
N_EO_bm 0.0
N_EO_i_aw 0.0
N_EO_i_b 0.0
N_EO_perc 0.0
OH_aw 0.0
OH_b 0.0
OL_ASM 0.0
OL_aw 0.0
OL_b 0.0
OL_b_ex 0.0
OOH_aw 0.0
OOH_b 0.0
PL 110.0
PLA2_Ca 0.0
PLA2_D 0.0
Q_AW_blf 5.23
R1_portion_EOa 0.39
R1_portion_FEV 0.016
R2_portion_FEV 0.037
REDOX_aw 0.0
REDOX_b 0.0
RELFLO5_aw 0.0
RELFLO5_b 0.0
R_FEV 3.007
R_Hn_AW 5130.0
R_Hn_B 141.0
R_LTC_AW 1.4
R_LTC_B 0.538
R_LTD_AW 1.4
R_LTD_B 0.538
R_LTE_AW 1.4
R_LTE_B 0.538
R_ZF_AW 2.96
R_ZF_B 0.533
R_in_relax_FEV 2.073
Rec_occup_migr 0.0
T 1440.0
TSN 0.0
TSN_0 15.5
TSN_Hn 0.0
V_CAW 0.0
V_CB 0.0
V_CoA 350.0
V_LTC_CAW 0.0
V_LTC_CB 0.0
V_aCAW 0.0
V_aCB 0.0
Vmax_PLA2 450.0
ZF_airways_conc 0.0
ZF_blood_conc 0.0
a 1.0
al 1.0
ca 10.0
delta_LTCs_aw 0.0
delta_LTCs_b 0.0
den_LTCs_aw 0.0
den_LTCs_b 0.0
diam_EO 0.00012
ft_ml 0.0
ft_zf 0.0
fup_Hn 0.77
fup_LT 0.16
fup_ML 0.004
fup_ZF 0.069
h_act 3.0
h_matur 1.0
h_migr 3.0
k1 0.000001
k1_min 0.00000016
k3 34.0
k_3 263640.0
k_EO_a_d 0.00015
k_EO_d 0.0003
k_EO_m 10.0
k_EO_t_baw 0.04
k_EO_t_bmb 0.02
k_Hn_d 0.033
k_Hn_p 18000000000.0
k_IL_d 0.0046
k_IL_p 16.0
k_IL_t_awb 0.05
k_IL_t_bbm 0.001
k_LTCs_back 1003.709
k_LTCs_fow 1068016.0
k_abs_ml 0.012
k_abs_zf 0.018
k_acet 0.002703885
k_dp 0.067
k_elim_ml 0.00225
k_elim_zf 0.004
k_fev_eff 3000000.0
k_ggt 0.1
k_gpx_cat 0.4884995
k_hedh_1 88.33768
k_hedh_2 1724.404
k_hedh_3 31.49749
k_hedh_4 8.077531
k_lo 4642.68
k_lta_syn 54420.0
k_ltc_ltd_el 0.1
k_lte_el 0.04
k_ox 0.0002658
k_ox2 67.2
k_red 0.0002538
k_red2 0.00004428
ka 500.0
ki 25000.0
kia 0.001
n_FEV 1.0
naEO_LTCsyn 0.0
nom_LTCs_aw 0.0
nom_LTCs_b 0.0
npi 3.14
oral 1.0
oxoETE_aw 0.0
oxoETE_b 0.0
portion_migr 0.3
r1 0.0
r2 0.0
r_in_FEV 0.0
r_out_FEV 0.0
time_day 0.0
time_hour 0.0
w_EO 0.0
zf_inh 0.0

Local parameters

Id Value Reaction

Rules 0   0   101

Assignment rules

Definition
ft_ml = ceil(time / T)
ZF_blood_conc = fup_ZF * ZF_blood
ZF_airways_conc = ZF_airways
ML_blood_conc = fup_ML * ML_blood
ML_airways_conc = fup_ML * ML_blood
w_EO = npi * pow(diam_EO, 3.000000e+00) / 6.000000e+00
V_aCB = EO_a_b * N_A_pmole * w_EO * V_B
V_aCAW = EO_a_aw * N_A_pmole * w_EO * V_AW
GSSG_b = (GS_pool_b - GSH_b) / 2.000000e+00
PLA2_D = 1.000000e+00 + Ca / K_PLA2_Ca
Ki_AA_AA = Ki_AA
Ki_HPETE_AA = Ki_AA
OOH_b = HPETE_b + LOOH_b
OH_b = HETE_b + LOH_b
r1 = k_ox + k_ox2 * Ca / K_Ca2
r2 = k_red + k_red2 * Ca / K_Ca2
RELFLO5_b = (k_lo * AA_b / K_AA + k3 * HPETE_b * (1.000000e+00 + AA_b / Ki_AA)) / (k_lta_syn + k_3 * (1.000000e+00 + AA_b / Ki_HPETE_AA))
FLO3_b = FLOa / DFLOa_b
FLO2_b = FLO3_b * REDOX_b
FLO3t_b = FLO3_b * (1.000000e+00 + Ca / K_Ca3)
FLO2t_b = FLO2_b * (1.000000e+00 + Ca / K_Ca2)
FLO5HP_b = FLO3t_b * RELFLO5_b
C_b = HPETE_b * GSH_b * GSH_b / (Km_gpx_HPETE5 * Km_gpx_GSH * Km_gpx_GSH)
delta_LTCs_b = 1.000000e+00 + LTA4_b / K_LTA + GSH_b / K_GSH + LTA4_b * GSH_b / K_LTA / K_LTA_GSH + LTC4_b / K_LTC
C_hedh_b = (1.000000e+00 + HETE_b / Kd_hedh_HETE5 + NADPH_b / Kd_hedh_NADPH) * (k_hedh_3 * oxoETE_b / Kd_hedh_oxoETE5 + k_hedh_2 * NADP_b / Kd_hedh_NADP)
GSSG_aw = (GS_pool_aw - GSH_aw) / 2.000000e+00
NADPH_aw = NP_pool_aw - NADP_aw
OOH_aw = HPETE_aw + LOOH_aw
OH_aw = HETE_aw + LOH_aw
RELFLO5_aw = (k_lo * AA_aw / K_AA + k3 * HPETE_aw * (1.000000e+00 + AA_aw / Ki_AA)) / (k_lta_syn + k_3 * (1.000000e+00 + AA_aw / Ki_HPETE_AA))
FLO3_aw = FLOa / DFLOa_aw
FLO2_aw = FLO3_aw * REDOX_aw
FLO3t_aw = FLO3_aw * (1.000000e+00 + Ca / K_Ca3)
FLO2t_aw = FLO2_aw * (1.000000e+00 + Ca / K_Ca2)
FLO5HP_aw = FLO3t_aw * RELFLO5_aw
C_aw = HPETE_aw * GSH_aw * GSH_aw / (Km_gpx_HPETE5 * Km_gpx_GSH * Km_gpx_GSH)
B_aw = k_gpx_cat * HPETE_aw * GSH_aw * GSH_aw / (Km_gpx_HPETE5 * Km_gpx_GSH * Km_gpx_GSH)
den_LTCs_aw = delta_LTCs_aw * K_LTA_GSH * K_GSH * K_LTC
C_hedh_aw = (1.000000e+00 + HETE_aw / Kd_hedh_HETE5 + NADPH_aw / Kd_hedh_NADPH) * (k_hedh_3 * oxoETE_aw / Kd_hedh_oxoETE5 + k_hedh_2 * NADP_aw / Kd_hedh_NADP)
B_hedh_aw = k_hedh_1 * k_hedh_2 * HETE_aw * NADP_aw / (Kd_hedh_HETE5 * Kd_hedh_NADP) - oxoETE_aw * NADPH_aw * k_hedh_3 * k_hedh_4 / (Kd_hedh_oxoETE5 * Kd_hedh_NADPH)
Rec_occup_migr = portion_migr * fup_LT * LTE4_b / (Kd_LTE_migr + fup_LT * LTE4_b) + (1.000000e+00 - portion_migr) * IL_b / (Kd_IL_migr + IL_b)
r_in_FEV = r_out_FEV - (R_FEV - R_in_relax_FEV) * pow(R_FEV / r_out_FEV, 5.000000e-01)
FEV1 = MAX_FEV * pow(r_in_FEV / R_in_relax_FEV, 2.000000e+00)
time_hour = time / 6.000000e+01
time_day = time / 1.440000e+03
N_EO_bm = EO_bm * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
N_EO_b = EO_b * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
N_EO_i_b = EO_i_b * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
EO_b_tot = EO_b + EO_i_b + EO_a_b
N_EO_b_tot = (EO_b + EO_i_b + EO_a_b) * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
N_EO_aw = EO_aw * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
N_EO_i_aw = EO_i_aw * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
N_EO_a_aw = EO_a_aw * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
EO_aw_tot = EO_aw + EO_i_aw + EO_a_aw
N_EO_aw_tot = (EO_aw + EO_i_aw + EO_a_aw) * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
EO_b_tot_per_ss = 1.000000e+02 * (EO_b_tot - 5.330000e-04) / 5.330000e-04
N_EO_aw_tot_perc = N_EO_aw_tot / 8.187350e+05 * 1.000000e+02
N_EO_b_tot_perc = N_EO_b_tot / 4.266021e+06 * 1.000000e+02
LTC4_b_pM = LTC4_b * 1.000000e+06
N_EO_a = (N_EO_a_b * V_B + N_EO_a_aw * V_AW) / (V_B + V_AW)
N_EO = (N_EO_b_tot * V_B + N_EO_aw_tot * V_AW) / (V_B + V_AW)
N_EO_aw_perc = 1.000000e+02 * N_EO_aw_tot / 8.187350e+05
Hn_aw_perc = 1.000000e+02 * Hn_aw / 1.416200e+04
N_EO_perc = 1.000000e+02 * N_EO / 3.587580e+05
OL_ASM = R1_portion_FEV * (LTD4_aw / Kd_LTR1_FEV) / (1.000000e+00 + LTD4_aw / Kd_LTR1_FEV + ML_airways_conc / EC50_ML_FEV) + R2_portion_FEV * ((LTD4_aw + LTC4_aw_out) / Kd_LTR2_FEV) / (1.000000e+00 + (LTD4_aw + LTC4_aw_out) / Kd_LTR2_FEV) + (1.000000e+00 - R1_portion_FEV - R2_portion_FEV) * (Hn_aw / Kd_Hn_FEV) / (1.000000e+00 + Hn_aw / Kd_Hn_FEV)
Ca_FEV_LTR2 = k_fev_eff * (R2_portion_FEV * ((LTD4_aw + LTC4_aw_out) / Kd_LTR2_FEV) / (1.000000e+00 + (LTD4_aw + LTC4_aw_out) / Kd_LTR2_FEV) + (1.000000e+00 - R1_portion_FEV - R2_portion_FEV) * (Hn_aw / Kd_Hn_FEV) / (1.000000e+00 + Hn_aw / Kd_Hn_FEV)) / (Ca_FEV - Cao_FEV)
Ca_FEV_LTR1 = k_fev_eff * (R1_portion_FEV * (LTD4_aw / Kd_LTR1_FEV) / (1.000000e+00 + LTD4_aw / Kd_LTR1_FEV + ML_airways_conc / EC50_ML_FEV)) / (Ca_FEV - Cao_FEV)
LTD4_aw_pers = 1.000000e+02 * LTD4_aw / 2.057600e+02
ML_uM = ML_blood / 1.000000e+06
LTD4_b_free = LTD4_b * fup_LT
LTs_aw_pg = (LTC4_aw_out / fup_LT * M_LTC + LTD4_aw / fup_LT * M_LTD + LTE4_aw / fup_LT * M_LTE) / 1.000000e+03
N_EO_a_b = EO_a_b * 6.020000e+00 * pow(1.000000e+01, 8.000000e+00)
FEV1_percent = (FEV1 - 3.528000e+00) / 3.528000e+00 * 1.000000e+02
TSN_Hn = TSN_0 * (R_FEV - pow(R_FEV * pow(R_FEV - R_in_relax_FEV, 2.000000e+00), 1.000000e+00 / 3.000000e+00)) * pow(Ca_FEV, n_FEV) / (pow(K_Ca_FEV, n_FEV) + pow(Ca_FEV, n_FEV))
TSN = TSN_0 * (R_FEV - pow(R_FEV * pow(R_FEV - R_in_relax_FEV, 2.000000e+00), 1.000000e+00 / 3.000000e+00)) * pow(Ca_FEV_ex, n_FEV) / (pow(K_Ca_FEV, n_FEV) + pow(Ca_FEV_ex, n_FEV))
r_out_FEV = R_FEV - (R_FEV - pow(R_FEV * pow(R_FEV - R_in_relax_FEV, 2.000000e+00), 1.000000e+00 / 3.000000e+00)) * pow(Ca_FEV, n_FEV) / (pow(K_Ca_FEV, n_FEV) + pow(Ca_FEV, n_FEV))
Ca_FEV = Cao_FEV + k_fev_eff * (R1_portion_FEV * (LTD4_aw / Kd_LTR1_FEV) / (1.000000e+00 + LTD4_aw / Kd_LTR1_FEV + ML_airways_conc / EC50_ML_FEV) + R2_portion_FEV * ((LTD4_aw + LTC4_aw_out) / Kd_LTR2_FEV) / (1.000000e+00 + (LTD4_aw + LTC4_aw_out) / Kd_LTR2_FEV) + (1.000000e+00 - R1_portion_FEV - R2_portion_FEV) * (Hn_aw / Kd_Hn_FEV) / (1.000000e+00 + Hn_aw / Kd_Hn_FEV))
OL_aw = R1_portion_EOa * (LTD4_aw / Kd_LT) / (1.000000e+00 + LTD4_aw / Kd_LT + ML_airways_conc / Ki_ML_EOa) + (1.000000e+00 - R1_portion_EOa) * ((LTC4_aw_out + LTD4_aw) / Kd_LT_2) / (1.000000e+00 + (LTC4_aw_out + LTD4_aw) / Kd_LT_2)
OL_b = R1_portion_EOa * (fup_LT * LTD4_b / Kd_LT) / (1.000000e+00 + fup_LT * LTD4_b / Kd_LT + ML_blood_conc / Ki_ML_EOa) + (1.000000e+00 - R1_portion_EOa) * (fup_LT * (LTC4_b_out + LTD4_b) / Kd_LT_2) / (1.000000e+00 + fup_LT * (LTC4_b_out + LTD4_b) / Kd_LT_2)
A_hedh_aw = (1.000000e+00 + NADP_aw / Kd_hedh_NADP + oxoETE_aw / Kd_hedh_oxoETE5) * (k_hedh_1 * HETE_aw / Kd_hedh_HETE5 + k_hedh_4 * NADPH_aw / Kd_hedh_NADPH) + C_hedh_aw
nom_LTCs_aw = Et_LTCs * (K_LTC * k_LTCs_fow * LTA4_aw * GSH_aw - k_LTCs_back * K_LTA_GSH * K_GSH * LTC4_aw)
delta_LTCs_aw = 1.000000e+00 + LTA4_aw / K_LTA + GSH_aw / K_GSH + LTA4_aw * GSH_aw / K_LTA / K_LTA_GSH + LTC4_aw / K_LTC
A_aw = GSH_aw * GSH_aw / (Km_gpx_GSH * Km_gpx_GSH) * (1.000000e+00 + GSSG_aw / Kd_gpx_GSSG) + HPETE_aw / Km_gpx_HPETE5 * (1.000000e+00 + HETE_aw / Kd_gpx_HETE5) + C_aw
DFLOa_aw = (1.000000e+00 + Ca / K_Ca3) * (1.000000e+00 + REDOX_aw * (1.000000e+00 + Ca / K_Ca2) / (1.000000e+00 + Ca / K_Ca3) + AA_aw / K_AA * (1.000000e+00 + AA_aw / Ki_AA_AA) + AA_aw / Ki_AA * (1.000000e+00 + HETE_aw / K_AA_HETE) + RELFLO5_aw * (1.000000e+00 + AA_aw / Ki_HPETE_AA) + HETE_aw / Ki_HETE + al * ZF_airways_conc / KdZ)
REDOX_aw = (r2 / Ke_red + r1 * OH_aw / Ke_ox + al * ki * ZF_airways_conc / KdZ * (1.000000e+00 + Ca / K_Ca3)) / (r2 + r1 * OOH_aw)
B_hedh_b = k_hedh_1 * k_hedh_2 * HETE_b * NADP_b / (Kd_hedh_HETE5 * Kd_hedh_NADP) - oxoETE_b * NADPH_b * k_hedh_3 * k_hedh_4 / (Kd_hedh_oxoETE5 * Kd_hedh_NADPH)
A_hedh_b = (1.000000e+00 + NADP_b / Kd_hedh_NADP + oxoETE_b / Kd_hedh_oxoETE5) * (k_hedh_1 * HETE_b / Kd_hedh_HETE5 + k_hedh_4 * NADPH_b / Kd_hedh_NADPH) + C_hedh_b
den_LTCs_b = delta_LTCs_b * K_LTA_GSH * K_GSH * K_LTC
nom_LTCs_b = Et_LTCs * (K_LTC * k_LTCs_fow * LTA4_b * GSH_b - k_LTCs_back * K_LTA_GSH * K_GSH * LTC4_b)
B_b = k_gpx_cat * HPETE_b * GSH_b * GSH_b / (Km_gpx_HPETE5 * Km_gpx_GSH * Km_gpx_GSH)
A_b = GSH_b * GSH_b / (Km_gpx_GSH * Km_gpx_GSH) * (1.000000e+00 + GSSG_b / Kd_gpx_GSSG) + HPETE_b / Km_gpx_HPETE5 * (1.000000e+00 + HETE_b / Kd_gpx_HETE5) + C_b
DFLOa_b = (1.000000e+00 + Ca / K_Ca3) * (1.000000e+00 + REDOX_b * (1.000000e+00 + Ca / K_Ca2) / (1.000000e+00 + Ca / K_Ca3) + AA_b / K_AA * (1.000000e+00 + AA_b / Ki_AA_AA) + AA_b / Ki_AA * (1.000000e+00 + HETE_b / K_AA_HETE) + RELFLO5_b * (1.000000e+00 + AA_b / Ki_HPETE_AA) + HETE_b / Ki_HETE + al * ZF_blood_conc / KdZ)
REDOX_b = (r2 / Ke_red + r1 * OH_b / Ke_ox + al * ki * ZF_blood_conc / KdZ * (1.000000e+00 + Ca / K_Ca3)) / (r2 + r1 * OOH_b)
K_AA_HETE = Ki_HETE
PLA2_Ca = Ca / K_PLA2_Ca / PLA2_D
NADPH_b = NP_pool_b - NADP_b
V_LTC_CAW = (naEO_LTCsyn * (EO_aw + EO_i_aw) + EO_a_aw) * N_A_pmole * w_EO * V_AW
V_CAW = (EO_a_aw + EO_aw + EO_i_aw) * N_A_pmole * w_EO * V_AW
V_LTC_CB = (naEO_LTCsyn * (EO_b + EO_i_b) + EO_a_b) * N_A_pmole * w_EO * V_B
V_CB = (EO_a_b + EO_b + EO_i_b) * N_A_pmole * w_EO * V_B
ft_zf = ceil(time / T) + ceil((time - 3.600000e+02) / T) + ceil((time - 6.600000e+02) / T) + ceil((time - 9.600000e+02) / T)

Rate rules

Definition

Algebraic rules

Definition

Events 0

Trigger Assignments