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BIOMD0000000512 - Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain

 

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Reference Publication
Publication ID: 24429592
Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH.
A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.
CPT Pharmacometrics Syst Pharmacol 2014; 3: e91
Xenologiq, Canterbury, Kent, UK.  [more]
Model
Original Model: BIOMD0000000512.origin
Submitter: Vijayalakshmi Chelliah
Submission ID: MODEL1402030000
Submission Date: 03 Feb 2014 11:47:16 UTC
Last Modification Date: 28 Apr 2014 16:59:55 UTC
Creation Date: 07 Feb 2014 11:43:50 UTC
Encoders:  Vijayalakshmi Chelliah
   Niel Benson
set #1
bqbiol:hasVersion Human Disease Ontology osteoarthritis
set #2
bqbiol:isVersionOf Gene Ontology fatty acid amide hydrolase activity
Gene Ontology endocannabinoid signaling pathway
bqbiol:hasTaxon Taxonomy Homo sapiens
bqbiol:hasProperty Mathematical Modelling Ontology ordinary differential equation model
Notes
Benson2014 - FAAH inhibitors for the treatment of osteoarthritic pain

Evaluation of fatty acid amide hydrolase (FAAH) as a target for osteoarthritic pain in humans, using an integrated systems pharmacology model.

The SBML version of the model is obtained from the supplementary material of the corresponding paper (see below).

This model is described in the article:

Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH.
CPT Pharmacometrics Syst Pharmacol. 2014 Jan 15;3:e91.

Abstract:

The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 24429592 Submission Date: 03 Feb 2014 11:47:16 UTC Last Modification Date: 28 Apr 2014 16:59:55 UTC Creation Date: 07 Feb 2014 11:43:50 UTC
Mathematical expressions
Reactions
vA_degr_b vO_degr_b vP_degr_b vL_degr_b
vS_degr_b vNAPE_syn_b vNOPE_syn_b vNPPE_syn_b
vNLPE_syn_b vNSPE_syn_b vA_syn_b vO_syn_b
vP_syn_b vL_syn_b vS_syn_b vFAAH_syn_b
vFAAH_degr_b vFAAH_inh_b vFAAH_inh_degr_b vA_UE_b
vO_UE_b vP_UE_b vL_UE_b vS_UE_b
vA_degr_r vO_degr_r vP_degr_r vL_degr_r
vS_degr_r vNAPE_syn_r vNOPE_syn_r vNPPE_syn_r
vNLPE_syn_r vNSPE_syn_r vA_syn_r vO_syn_r
vP_syn_r vL_syn_r vS_syn_r vFAAH_syn_r
vFAAH_degr_r vFAAH_inh_r vFAAH_inh_degr_r vA_UE_r
vO_UE_r vP_UE_r vL_UE_r vS_UE_r
vA_degr_m vO_degr_m vP_degr_m vL_degr_m
vS_degr_m vFAAH_syn_m vFAAH_degr_m vFAAH_inh_m
vFAAH_inh_degr_m vA_m_p vo_m_p vP_m_p
vL_m_p vS_m_p vA_b_m vO_b_m
vP_b_m vL_b_m vS_b_m vA_r_p
vO_r_p vP_r_p vL_r_p vS_r_p
absorp dist elim  
Rules
Assignment Rule (variable: F_PFM) Assignment Rule (variable: MD) Assignment Rule (variable: PF_p) Assignment Rule (variable: PF_b)
Assignment Rule (variable: PF_r) Assignment Rule (variable: PF_m) Assignment Rule (variable: FAAH_D_b) Assignment Rule (variable: slag1_b)
Assignment Rule (variable: slag2_b) Assignment Rule (variable: den_b) Assignment Rule (variable: FAAH_D_r) Assignment Rule (variable: c_NAT_ROB)
Assignment Rule (variable: slag1_r) Assignment Rule (variable: slag2_r) Assignment Rule (variable: den_r) Assignment Rule (variable: c_FAAH_ROB)
Assignment Rule (variable: c_NAAA_ROB) Assignment Rule (variable: FAAH_D_m) Assignment Rule (variable: F_r) Assignment Rule (variable: PFG_p)
Assignment Rule (variable: AG_p) Assignment Rule (variable: OG_p) Assignment Rule (variable: PG_p) Assignment Rule (variable: LG_p)
Assignment Rule (variable: SG_p) Assignment Rule (variable: CB1_b) Assignment Rule (variable: tid)  
Physical entities
Compartments Species
Default PFM_gut PFM_p PFM_r
BRAIN A_b O_b P_b
L_b S_b NAPE_b
NOPE_b NPPE_b NLPE_b
NSPE_b FAAH_b FAAHinh_b
     
PLASMA A_p O_p P_p
L_p S_p  
ROB A_r O_r P_r
L_r S_r NAPE_r
NOPE_r NPPE_r NLPE_r
NSPE_r FAAH_r FAAHinh_r
     
MEC A_m O_m P_m
L_m S_m FAAH_m
FAAHinh_m    
Global parameters
AG2_b Dose ED50 Emax_PFM
FAAH_t Gut H Heart
Kd_AG2 Kd_CB1_A Ki_A Ki_L
Ki_O Ki_P Ki_S Kidney
Km_FAAH_A Km_FAAH_L Km_FAAH_O Km_FAAH_P
Km_FAAH_S Km_NA_PE Km_NL_PE Km_NO_PE
Km_NP_PE Km_NS_PE Km_PFM Km_p_m_A
Kp_b_PF Kp_m_PF Kp_r_PF Ktr_p_m_A
Ktr_p_m_L Ktr_p_m_O Ktr_p_m_P Ktr_p_m_S
Ktr_p_r_A Ktr_p_r_L Ktr_p_r_O Ktr_p_r_P
Ktr_p_r_S LEU LIVER Leucocytes
Lungs M_A M_L M_O
M_P M_PF M_S Muscles
PLD_b PLD_r Pancreas R_PF
Spleen Testis Thymus Vm_PFM
Vmax_NAT Vss_PFM a_FAAH_A a_FAAH_L
a_FAAH_O a_FAAH_P a_FAAH_S a_NAT_A
a_NAT_L a_NAT_O a_NAT_P a_NAT_S
b_FAAH_Brain b_FAAH_Gut b_FAAH_Kidney b_FAAH_Leucocytes
b_FAAH_Liver b_FAAH_Lungs b_FAAH_MEC b_FAAH_Spleen
b_FAAH_Testis b_NAAA_Brain b_NAAA_Gut b_NAAA_Heart
b_NAAA_Kidney b_NAAA_Liver b_NAAA_Lungs b_NAAA_Spleen
b_NAAA_Testis b_NAAA_Thymus b_NAT_Brain b_NAT_Heart
b_NAT_Kidney b_NAT_Leucocytes b_NAT_Lungs b_NAT_Muscles
b_NAT_Pancreas b_NAT_Testis e1 k_NA_PE
k_NL_PE k_NO_PE k_NP_PE k_NS_PE
k_deg_FAAH k_inh kabs_PFM kcat_FAAH
kcl_A kcl_L kcl_O kcl_P
kcl_S kin_PFM klinear_PFM kout_PFM
ktr_m_p_A ktr_m_p_L ktr_m_p_O ktr_m_p_P
ktr_m_p_S ktr_r_p p_A p_L
p_O p_P p_S t
F_PFM MD PF_p PF_b
PF_r PF_m FAAH_D_b slag1_b
slag2_b den_b FAAH_D_r c_NAT_ROB
slag1_r slag2_r den_r c_FAAH_ROB
c_NAAA_ROB FAAH_D_m F_r PFG_p
AG_p OG_p PG_p LG_p
SG_p CB1_b tid  
Reactions (75)
 
 vA_degr_b [A_b] → ;   {FAAH_b} , {FAAH_b} , {A_b}
 
 vO_degr_b [O_b] → ;   {FAAH_b} , {FAAH_b} , {O_b}
 
 vP_degr_b [P_b] → ;   {FAAH_b} , {FAAH_b} , {P_b}
 
 vL_degr_b [L_b] → ;   {FAAH_b} , {FAAH_b} , {L_b}
 
 vS_degr_b [S_b] → ;   {FAAH_b} , {FAAH_b} , {S_b}
 
 vNAPE_syn_b  → [NAPE_b];  
 
 vNOPE_syn_b  → [NOPE_b];  
 
 vNPPE_syn_b  → [NPPE_b];  
 
 vNLPE_syn_b  → [NLPE_b];  
 
 vNSPE_syn_b  → [NSPE_b];  
 
 vA_syn_b [NAPE_b] → [A_b];   {NAPE_b}
 
 vO_syn_b [NOPE_b] → [O_b];   {NOPE_b}
 
 vP_syn_b [NPPE_b] → [P_b];   {NPPE_b}
 
 vL_syn_b [NLPE_b] → [L_b];   {NLPE_b}
 
 vS_syn_b [NSPE_b] → [S_b];   {NSPE_b}
 
 vFAAH_syn_b  → [FAAH_b];  
 
 vFAAH_degr_b [FAAH_b] → ;   {FAAH_b}
 
 vFAAH_inh_b [FAAH_b] → [FAAHinh_b];   {FAAH_b}
 
 vFAAH_inh_degr_b [FAAHinh_b] → ;   {FAAHinh_b}
 
 vA_UE_b [A_b] → ;   {A_b}
 
 vO_UE_b [O_b] → ;   {O_b}
 
 vP_UE_b [P_b] → ;   {P_b}
 
 vL_UE_b [L_b] → ;   {L_b}
 
 vS_UE_b [S_b] → ;   {S_b}
 
 vA_degr_r [A_r] → ;   {FAAH_r} , {FAAH_r} , {A_r}
 
 vO_degr_r [O_r] → ;   {FAAH_r} , {FAAH_r} , {O_r}
 
 vP_degr_r [P_r] → ;   {FAAH_r} , {FAAH_r} , {P_r}
 
 vL_degr_r [L_r] → ;   {FAAH_r} , {FAAH_r} , {L_r}
 
 vS_degr_r [S_r] → ;   {FAAH_r} , {FAAH_r} , {S_r}
 
 vNAPE_syn_r  → [NAPE_r];  
 
 vNOPE_syn_r  → [NOPE_r];  
 
 vNPPE_syn_r  → [NPPE_r];  
 
 vNLPE_syn_r  → [NLPE_r];  
 
 vNSPE_syn_r  → [NSPE_r];  
 
 vA_syn_r [NAPE_r] → [A_r];   {NAPE_r}
 
 vO_syn_r [NOPE_r] → [O_r];   {NOPE_r}
 
 vP_syn_r [NPPE_r] → [P_r];   {NPPE_r}
 
 vL_syn_r [NLPE_r] → [L_r];   {NLPE_r}
 
 vS_syn_r [NSPE_r] → [S_r];   {NSPE_r}
 
 vFAAH_syn_r  → [FAAH_r];  
 
 vFAAH_degr_r [FAAH_r] → ;   {FAAH_r}
 
 vFAAH_inh_r [FAAH_r] → [FAAHinh_r];   {FAAH_r}
 
 vFAAH_inh_degr_r [FAAHinh_r] → ;   {FAAHinh_r}
 
 vA_UE_r [A_r] → ;   {A_r}
 
 vO_UE_r [O_r] → ;   {O_r}
 
 vP_UE_r [P_r] → ;   {P_r}
 
 vL_UE_r [L_r] → ;   {L_r}
 
 vS_UE_r [S_r] → ;   {S_r}
 
 vA_degr_m [A_m] → ;   {FAAH_m} , {FAAH_m} , {A_m}
 
 vO_degr_m [O_m] → ;   {FAAH_m} , {FAAH_m} , {O_m}
 
 vP_degr_m [P_m] → ;   {FAAH_m} , {FAAH_m} , {P_m}
 
 vL_degr_m [L_m] → ;   {FAAH_m} , {FAAH_m} , {L_m}
 
 vS_degr_m [S_m] → ;   {FAAH_m} , {FAAH_m} , {S_m}
 
 vFAAH_syn_m  → [FAAH_m];  
 
 vFAAH_degr_m [FAAH_m] → ;   {FAAH_m}
 
 vFAAH_inh_m [FAAH_m] → [FAAHinh_m];   {FAAH_m}
 
 vFAAH_inh_degr_m [FAAHinh_m] → ;   {FAAHinh_m}
 
 vA_m_p [A_m] → [A_p];   {A_m} , {A_p}
 
 vo_m_p [O_m] → [O_p];   {O_m} , {O_p}
 
 vP_m_p [P_m] → [P_p];   {P_m} , {P_p}
 
 vL_m_p [L_m] → [L_p];   {L_m} , {L_p}
 
 vS_m_p [S_m] → [S_p];   {S_m} , {S_p}
 
 vA_b_m [A_b] → [A_m];   {A_b} , {A_m}
 
 vO_b_m [O_b] → [O_m];   {O_b} , {O_m}
 
 vP_b_m [P_b] → [P_m];   {P_b} , {P_m}
 
 vL_b_m [L_b] → [L_m];   {L_b} , {L_m}
 
 vS_b_m [S_b] → [S_m];   {S_b} , {S_m}
 
 vA_r_p [A_r] → [A_p];   {A_r} , {A_p}
 
 vO_r_p [O_r] → [O_p];   {O_r} , {O_p}
 
 vP_r_p [P_r] → [P_p];   {P_r} , {P_p}
 
 vL_r_p [L_r] → [L_p];   {L_r} , {L_p}
 
 vS_r_p [S_r] → [S_p];   {S_r} , {S_p}
 
 absorp [PFM_gut] → [PFM_p];  
 
 dist [PFM_p] → [PFM_r];   {PFM_p} , {PFM_r}
 
 elim [PFM_p] → ;   {PFM_p}
 
Rules (27)
 
 Assignment Rule (name: F_PFM) F_PFM = Emax_PFM*Dose/(ED50+Dose)
 
 Assignment Rule (name: MD) MD = PFM_gut+1E6*Dose*F_PFM
 
 Assignment Rule (name: PF_p) PF_p = 1.0/M_PF*PFM_p/Vss_PFM
 
 Assignment Rule (name: PF_b) PF_b = PF_p*Kp_b_PF
 
 Assignment Rule (name: PF_r) PF_r = PF_p*Kp_r_PF
 
 Assignment Rule (name: PF_m) PF_m = PF_p*Kp_m_PF
 
 Assignment Rule (name: FAAH_D_b) FAAH_D_b = 1.0+A_b/Km_FAAH_A+O_b/Km_FAAH_O+P_b/Km_FAAH_P+L_b/Km_FAAH_L+S_b/Km_FAAH_S
 
 Assignment Rule (name: slag1_b) slag1_b = NAPE_b/Km_NA_PE+NOPE_b/Km_NO_PE+NPPE_b/Km_NP_PE+NLPE_b/Km_NL_PE+NSPE_b/Km_NS_PE
 
 Assignment Rule (name: slag2_b) slag2_b = A_b/Ki_A+O_b/Ki_O+P_b/Ki_P+L_b/Ki_L+S_b/Ki_S
 
 Assignment Rule (name: den_b) den_b = 1.0+slag1_b+slag2_b
 
 Assignment Rule (name: FAAH_D_r) FAAH_D_r = 1.0+A_r/Km_FAAH_A+O_r/Km_FAAH_O+P_r/Km_FAAH_P+L_r/Km_FAAH_L+S_r/Km_FAAH_S
 
 Assignment Rule (name: c_NAT_ROB) c_NAT_ROB = Pancreas*b_NAT_Pancreas+Kidney*b_NAT_Kidney+Heart*b_NAT_Heart+Lungs*b_NAT_Lungs+Muscles*b_NAT_Muscles+Testis*b_NAT_Testis+Leucocytes*b_NAT_Leucocytes
 
 Assignment Rule (name: slag1_r) slag1_r = NAPE_r/Km_NA_PE+NOPE_r/Km_NO_PE+NPPE_r/Km_NP_PE+NLPE_r/Km_NL_PE+NSPE_r/Km_NS_PE
 
 Assignment Rule (name: slag2_r) slag2_r = A_r/Ki_A+O_r/Ki_O+P_r/Ki_P+L_r/Ki_L+S_r/Ki_S
 
 Assignment Rule (name: den_r) den_r = 1.0+slag1_r+slag2_r
 
 Assignment Rule (name: c_FAAH_ROB) c_FAAH_ROB = LIVER*b_FAAH_Liver+Gut*b_FAAH_Gut+Spleen*b_FAAH_Spleen+Kidney*b_FAAH_Kidney+Lungs*b_FAAH_Lungs+Testis*b_FAAH_Testis+Leucocytes*b_FAAH_Leucocytes
 
 Assignment Rule (name: c_NAAA_ROB) c_NAAA_ROB = LIVER*b_NAAA_Liver+Gut*b_NAAA_Gut+Spleen*b_NAAA_Spleen+Kidney*b_NAAA_Kidney+Heart*b_NAAA_Heart+Lungs*b_NAAA_Lungs+Thymus*b_NAAA_Thymus+Testis*b_NAAA_Thymus*Testis
 
 Assignment Rule (name: FAAH_D_m) FAAH_D_m = 1.0+A_m/Km_FAAH_A+O_m/Km_FAAH_O+P_m/Km_FAAH_P+L_m/Km_FAAH_L+S_m/Km_FAAH_S
 
 Assignment Rule (name: F_r) F_r = 1.5E3*FAAH_r/(FAAHinh_r+FAAH_r)
 
 Assignment Rule (name: PFG_p) PFG_p = 1E-3*PFM_p/Vss_PFM
 
 Assignment Rule (name: AG_p) AG_p = 1E-3*A_p*M_A
 
 Assignment Rule (name: OG_p) OG_p = 1E-3*O_p*M_O
 
 Assignment Rule (name: PG_p) PG_p = 1E-3*P_p*M_P
 
 Assignment Rule (name: LG_p) LG_p = 1E-3*L_p*M_L
 
 Assignment Rule (name: SG_p) SG_p = 1E-3*S_p*M_S
 
 Assignment Rule (name: CB1_b) CB1_b = (A_b/Kd_CB1_A+AG2_b/Kd_AG2)/(1.0+A_b/Kd_CB1_A+AG2_b/Kd_AG2)
 
 Assignment Rule (name: tid) tid = t/2.4E1
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 PFM_gut
Compartment: Default
Initial concentration: 0.0
 
 PFM_p
Compartment: Default
Initial concentration: 0.0
 
 PFM_r
Compartment: Default
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 1.45000004768372
 
 A_b
Compartment: BRAIN
Initial concentration: 0.7493309
 
 O_b
Compartment: BRAIN
Initial concentration: 20.77858
 
 P_b
Compartment: BRAIN
Initial concentration: 6.541209
 
 L_b
Compartment: BRAIN
Initial concentration: 2.319571
 
 S_b
Compartment: BRAIN
Initial concentration: 3.427807
 
 NAPE_b
Compartment: BRAIN
Initial concentration: 3.879041E-5
 
 NOPE_b
Compartment: BRAIN
Initial concentration: 8.814287E-4
 
 NPPE_b
Compartment: BRAIN
Initial concentration: 1.732296E-4
 
 NLPE_b
Compartment: BRAIN
Initial concentration: 7.550331E-5
 
 NSPE_b
Compartment: BRAIN
Initial concentration: 1.272629E-4
 
 FAAH_b
Compartment: BRAIN
Initial concentration: 15.366
 
 FAAHinh_b
Compartment: BRAIN
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 2.6489999294281
 
 A_p
Compartment: PLASMA
Initial concentration: 0.8740574
 
 O_p
Compartment: PLASMA
Initial concentration: 5.085073
 
 P_p
Compartment: PLASMA
Initial concentration: 4.849307
 
 L_p
Compartment: PLASMA
Initial concentration: 1.916254
 
 S_p
Compartment: PLASMA
Initial concentration: 0.273772
 
  Spatial dimensions: 3.0  Compartment size: 65.3000030517578
 
 A_r
Compartment: ROB
Initial concentration: 0.5419204
 
 O_r
Compartment: ROB
Initial concentration: 14.23822
 
 P_r
Compartment: ROB
Initial concentration: 4.121915
 
 L_r
Compartment: ROB
Initial concentration: 1.705466
 
 S_r
Compartment: ROB
Initial concentration: 2.515968
 
 NAPE_r
Compartment: ROB
Initial concentration: 4.241633E-6
 
 NOPE_r
Compartment: ROB
Initial concentration: 9.638198E-5
 
 NPPE_r
Compartment: ROB
Initial concentration: 1.894222E-5
 
 NLPE_r
Compartment: ROB
Initial concentration: 8.256095E-6
 
 NSPE_r
Compartment: ROB
Initial concentration: 1.391587E-5
 
 FAAH_r
Compartment: ROB
Initial concentration: 2.165868
 
 FAAHinh_r
Compartment: ROB
Initial concentration: 0.0
 
  Spatial dimensions: 3.0  Compartment size: 1.49999996210681E-5
 
 A_m
Compartment: MEC
Initial concentration: 0.97761
 
 O_m
Compartment: MEC
Initial concentration: 16.3219
 
 P_m
Compartment: MEC
Initial concentration: 5.809415
 
 L_m
Compartment: MEC
Initial concentration: 0.0
 
 S_m
Compartment: MEC
Initial concentration: 2.968774
 
 FAAH_m
Compartment: MEC
Initial concentration: 10.686
 
 FAAHinh_m
Compartment: MEC
Initial concentration: 0.0
 
Global Parameters (155)
 
   AG2_b  
 
   Dose
Value: 10.0
 
   ED50
Value: 0.53
 
   Emax_PFM
Value: 0.773
 
   FAAH_t
Value: 78.0
 
   Gut
Value: 1.65
 
   H
Value: 0.48
 
   Heart
Value: 0.31
 
   Kd_AG2
Value: 3424.0
 
   Kd_CB1_A
Value: 239.2
 
   Ki_A
Value: 230.0
 
   Ki_L
Value: 1000.0
 
   Ki_O
Value: 240.0
 
   Ki_P
Value: 6700.0
 
   Ki_S
Value: 840.0
 
   Kidney
Value: 0.28
 
   Km_FAAH_A
Value: 8200.0
 
   Km_FAAH_L
Value: 10800.0
 
   Km_FAAH_O
Value: 52200.0
 
   Km_FAAH_P
Value: 543000.0
 
   Km_FAAH_S
Value: 10000.0
 
   Km_NA_PE
Value: 2800.0
 
   Km_NL_PE
Value: 1000.0
 
   Km_NO_PE
Value: 2900.0
 
   Km_NP_PE
Value: 3300.0
 
   Km_NS_PE
Value: 3400.0
 
   Km_PFM
Value: 26.1
 
   Km_p_m_A
Value: 1.0
 
   Kp_b_PF
Value: 1.3
 
   Kp_m_PF
Value: 1.3
 
   Kp_r_PF
Value: 1.5
 
   Ktr_p_m_A
Value: 1.89
 
   Ktr_p_m_L
Value: 2.77
 
   Ktr_p_m_O
Value: 9.07
 
   Ktr_p_m_P
Value: 2.65
 
   Ktr_p_m_S
Value: 30.01
 
   Ktr_p_r_A
Value: 0.62
 
   Ktr_p_r_L
Value: 0.89
 
   Ktr_p_r_O
Value: 2.8
 
   Ktr_p_r_P
Value: 0.85
 
   Ktr_p_r_S
Value: 9.19
 
   LEU
Value: 0.025
 
   LIVER
Value: 1.69
 
   Leucocytes
Value: 0.025
 
   Lungs
Value: 1.172
 
   M_A
Value: 347.5
 
   M_L
Value: 323.5
 
   M_O
Value: 325.5
 
   M_P
Value: 299.5
 
   M_PF
Value: 455.4
 
   M_S
Value: 321.5
 
   Muscles
Value: 35.0
 
   PLD_b
Value: 1.0E7
 
   PLD_r
Value: 1.0E7
 
   Pancreas
Value: 0.077
 
   R_PF
Value: 0.6
 
   Spleen
Value: 0.192
 
   Testis
Value: 0.036
 
   Thymus
Value: 0.029
 
   Vm_PFM
Value: 1511.0
 
   Vmax_NAT
Value: 300.0
 
   Vss_PFM
Value: 58.328
 
   a_FAAH_A
Value: 1.0
 
   a_FAAH_L
Value: 1.15
 
   a_FAAH_O
Value: 5.7
 
   a_FAAH_P
Value: 37.8
 
   a_FAAH_S
Value: 1.0
 
   a_NAT_A
Value: 1.0
 
   a_NAT_L
Value: 8.6
 
   a_NAT_O
Value: 13.0
 
   a_NAT_P
Value: 0.42
 
   a_NAT_S
Value: 1.0
 
   b_FAAH_Brain
Value: 0.197
 
   b_FAAH_Gut
Value: 0.034
 
   b_FAAH_Kidney
Value: 0.069
 
   b_FAAH_Leucocytes  
 
   b_FAAH_Liver
Value: 1.0
 
   b_FAAH_Lungs
Value: 0.032
 
   b_FAAH_MEC
Value: 0.137
 
   b_FAAH_Spleen
Value: 0.03
 
   b_FAAH_Testis
Value: 0.126
 
   b_NAAA_Brain
Value: 0.6
 
   b_NAAA_Gut
Value: 0.2
 
   b_NAAA_Heart
Value: 0.2
 
   b_NAAA_Kidney
Value: 0.6
 
   b_NAAA_Liver
Value: 1.0
 
   b_NAAA_Lungs
Value: 14.0
 
   b_NAAA_Spleen
Value: 8.0
 
   b_NAAA_Testis
Value: 0.6
 
   b_NAAA_Thymus
Value: 4.0
 
   b_NAT_Brain
Value: 1.667
 
   b_NAT_Heart
Value: 1.0
 
   b_NAT_Kidney
Value: 0.667
 
   b_NAT_Leucocytes  
 
   b_NAT_Lungs
Value: 0.033
 
   b_NAT_Muscles
Value: 0.333
 
   b_NAT_Pancreas
Value: 0.333
 
   b_NAT_Testis
Value: 0.667
 
   e1
Constant
 
   k_NA_PE
Value: 202.0
 
   k_NL_PE
Value: 100.0
 
   k_NO_PE
Value: 230.0
 
   k_NP_PE
Value: 270.0
 
   k_NS_PE
Value: 280.0
 
   k_deg_FAAH
Value: 0.0051
 
   k_inh
Value: 1.1
 
   kabs_PFM
Value: 2.2
 
   kcat_FAAH
Value: 18000.0
 
   kcl_A
Value: 1.74
 
   kcl_L
Value: 1.25
 
   kcl_O
Value: 2.5
 
   kcl_P
Value: 2.61
 
   kcl_S
Value: 1.2
 
   kin_PFM
Value: 0.117
 
   klinear_PFM
Value: 0.0803
 
   kout_PFM
Value: 0.18
 
   ktr_m_p_A
Value: 150.0
 
   ktr_m_p_L  
 
   ktr_m_p_O
Value: 10.0
 
   ktr_m_p_P
Value: 10.0
 
   ktr_m_p_S
Value: 10.0
 
   ktr_r_p
Value: 100.0
 
   p_A
Value: 0.051
 
   p_L
Value: 0.016
 
   p_O
Value: 0.098
 
   p_P
Value: 0.615
 
   p_S
Value: 0.191
 
   t
Constant
 
   F_PFM  
 
   MD  
 
   PF_p  
 
   PF_b  
 
   PF_r  
 
   PF_m  
 
   FAAH_D_b  
 
   slag1_b  
 
   slag2_b  
 
   den_b  
 
   FAAH_D_r  
 
   c_NAT_ROB  
 
   slag1_r  
 
   slag2_r  
 
   den_r  
 
   c_FAAH_ROB  
 
   c_NAAA_ROB  
 
   FAAH_D_m  
 
   F_r  
 
   PFG_p  
 
   AG_p  
 
   OG_p  
 
   PG_p  
 
   LG_p  
 
   SG_p  
 
   CB1_b  
 
   tid  
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000512

Curator's comment: (updated: 07 Feb 2014 11:43:14 GMT)

Figure 5 of the reference publication has been reproduced here. The plots shows cannabinoid receptor (CB1) occupancy (in percentage) in the brain with the increasing dosage of drug (0.1 to 40mg). The model as such reproduces the plot corresponding to 10mg dose. Other plots were obtained by varying the value of the parameter "Dose".

The model was simulated using Copasi V4.11 (Build 64). The plots was generated using Gnuplot.

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