PROGRAM atra human

INITIAL

! tissue volumes

CONSTANT BW = 70. ! body weight {kg}

CONSTANT VFc = 0.214 ! fraction of fat tissue

CONSTANT VLc = 0.026 ! fraction of liver tissue

CONSTANT VBrc = 0.020 ! fraction of brain tissue

CONSTANT VHc = 0.005 ! fraction of heart tissue

CONSTANT VKc = 0.004 ! fraction of kidney tissue

CONSTANT VLuc = 0.008 ! fraction of lung tissue

CONSTANT VMc = 0.4 ! fraction of muscle tissue

CONSTANT VBc = 0.079 ! fraction of blood

! fraction of rest of body tissue

VRc = 0.986 - VFc - VLc - VBrc - VHc - VKc - VLuc - VMc - VBc

VF =VFc*BW ! {L or kg}

VL =VLc*BW

VBr = VBrc*BW

VH =VHc*BW

VK =VKc*BW

VLu = VLuc*BW

VM =VMc*BW

VB =VBc*BW

VR =VRc*BW

!------

!blood flow rates

CONSTANT QC = 365 ! {L/h} cardiac output

CONSTANT QFc = 0.052 ! fraction of blood flow to fat

CONSTANT QLc = 0.227 ! fraction of blood flow to liver

CONSTANT QBrc = 0.114 ! fraction of blood flow to brain

CONSTANT QHc = 0.04 ! fraction of blood flow to heart

CONSTANT QKc = 0.175 ! fraction of blood flow to kidney

CONSTANT QLuc = 0.025 ! fraction of blood flow to lung

CONSTANT QMc = 0.191 ! fraction of blood flow to muscle

! fraction of blood flow to rest of body

QRc = 1 - QFc - QLc - QBrc - QHc - QKc - QLuc - QMc

QF =QFc*QC

QL =QLc*QC

QBr = QBrc*QC

QH =QHc*QC

QK =QKc*QC

QLu = QLuc*QC

QM =QMc*QC

QR =QRc*QC

! ------

! Intestinal lumen volumes, surfaces, absorption rates, transfer rates

CONSTANT Papp = 28E-3 ! apparent intestinal permeability coefficient {dm/h}

CONSTANT ksto = 2.8 ! stomach emptying rate {/h}

CONSTANT kin = 2.19 ! Intestinal transfer rate

CONSTANT SAin = 10.3 ! Surface area 1/7 intestine

CONSTANT Vdd = 1.29 ! duodenum volume {L}

SAdd =SAin ! surface area {dm2}

kabdd = Papp*SAdd ! absorption rate constant {L/h}

kdd = kin ! transfer rate to jj1 {/h}

CONSTANT Vjj1 = 1.29 ! jejunum 1 volume {L}

SAjj1 = SAin ! surface area {dm2}

kabjj1 = Papp*SAjj1 ! absorption rate constant {L/h}

kjj1 = kin ! transfer rate to jj2 {/h}

CONSTANT Vjj2 = 1.29 ! jejunum 2 volume {L}

SAjj2 = SAin ! surface area {dm2}

kabjj2 = Papp*SAjj2 ! absorption rate constant {L/h}

kjj2 = kin ! transfer rate to jj3 {/h}

CONSTANT Vjj3 = 1.29 ! jejunum 3 volume {L}

SAjj3 = SAin ! surface area {dm2}

kabjj3 = Papp*SAjj3 ! absorption rate constant {L/h}

kjj3 = kin ! transfer rate to jj4 {/h}

CONSTANT Vjj4 = 1.29 ! jejunum 4 volume {L}

SAjj4 = SAin ! surface area {dm2}

kabjj4 = Papp*SAjj4 ! absorption rate constant {L/h}

kjj4 = kin ! transfer rate to jj5 {/h}

CONSTANT Vjj5 = 1.29 ! jejunum 5 volume {L}

SAjj5 = SAin ! surface area {dm2}

kabjj5 = Papp*SAjj5 ! absorption rate constant {L/h}

kjj5 = kin ! transfer rate to il {/h}

CONSTANT Vil = 1.29 ! ileum volume {L}

SAil =SAin ! surface area {dm2}

kabil = Papp*SAil ! absorption rate constant {L/h}

kil = kin ! transfer rate to co {/h}

CONSTANT kfe = 0.02 ! transfer rate to feces {/h}

!======

!Partition Coefficients

!======

CONSTANT PF = 6.8 ! fat:blood partition coefficient

CONSTANT PL = 3.6 ! liver:blood partition coefficient

CONSTANT PBr = 14 ! brain:blood partition coefficient

CONSTANT PH = 2 ! heart:blood partition coefficient

CONSTANT PK = 5.6 ! kidney:blood partition coefficient

CONSTANT PLu = 3.9 ! lung:blood partition coefficient

CONSTANT PM = 3.5 ! muscle:blood partition coefficient

CONSTANT PR = 1 ! rest of body:blood partition coefficient

CONSTANT Rbp = 0.67

!------

!Metabolism liver

!TODO: CYP expression are mu (log expr)

CONSTANT MPPGL = 33. ! mg microsomal protein per gram liver

!Metabolism liver

!metabolites of all-trans-retinoic acid, scaled maximum rate of metabolism (umol/h)

CONSTANT VmaxL2C8c = 4.8 ! (pmol/min/pmol CYP enzyme)

CONSTANT CYP2C8 = 27.1

VMaxL2C8 = VmaxL2C8c/1000000*60*MPPGL*CYP2C8*VL*1000

CONSTANT VmaxL3A4c = 4.0 ! (pmol/min/pmol CYP enzyme)

CONSTANT CYP3A4 = 54.6

VMaxL3A4 = VmaxL3A4c/1000000*60*MPPGL*CYP3A4*VL*1000

CONSTANT VmaxL3A5c = 4.9 ! (pmol/min/pmol CYP enzyme)

CONSTANT CYP3A5 = 11.0

VMaxL3A5 = VmaxL3A5c/1000000*60*MPPGL*CYP3A5*VL*1000

CONSTANT VmaxL3A7c = 2.3 ! (pmol/min/pmol CYP enzyme)

CONSTANT CYP3A7 = 1.19

VMaxL3A7 = VmaxL3A7c/1000000*60*MPPGL*CYP3A7*VL*1000

CONSTANT CYP26A1 = 0.20

CONSTANT VmaxL26A1c = 11. ! (pmol/min/pmol CYP enzyme)

VmaxL26A1 = VmaxL26A1c/1000000*60*MPPGL*CYP26A1*VL*1000

CONSTANT VMaxLtragc = 523 ! (pmol/min/mg UGT2B7)

CONSTANT UGT = 0.020

VMaxLtrag = VMaxLTragc/1000000*60*MPPGL*UGT*VL*1000

!metabolites of all-trans-retinoic acid, affinity constants (umol/L)

CONSTANT KmL2C8 = 13.4

CONSTANT KmL3A4 = 19.4

CONSTANT KmL3A5 = 11.1

CONSTANT KmL3A7 = 11.3

CONSTANT KmL26A1 = 0.0093

CONSTANT KmLtrag = 1.3

!------

!======

! Dosing

!======

!Molecular weight

CONSTANT MWtra = 300.4 ! Molecular weight

!Dosing

CONSTANT GDOSE = 0 ! GDOSE = given oral dose {mg/kg bw}

GDOSE2 = GDOSE*1E-3/MWtra*1E6 ! GDOSE2 = given oral dose converted to umol/kg

ODOSE = GDOSE2*BW ! ODOSE = umol

CONSTANT GIVDOSE = 0. ! GIVDOSE = given IV dose{mg/kg bw}

GIVDOSE2 = GIVDOSE*1E-3/MWtra*1E6 ! GIVDOSE2 = given IV dose converted to umol/kg

IVDOSE = GIVDOSE2*BW ! IVDOSE = umol

! Initial values state variables

Ast0 = ODOSE

AB0 = IVDOSE

END ! INITIAL

DYNAMIC

ALGORITHM IALG = 4

NSTEPS NSTP = 10

MAXTERVAL MAXT = 1.0e9

MINTERVAL MINT = 1.0e-9

CINTERVAL CINT = 0.1

DERIVATIVE

!stomach

!ASt = amount in stomach

dAst = -ksto*Ast

Ast = INTEG(dAst, Ast0)

!------

!intestines, divided in 7 compartments

!Add = Amount all-trans-retinoic acid in duodenum compartment(umol)

Cdd = Add/Vdd

dAdd =ksto*Ast - kdd*Add - kabdd*Cdd

Add = INTEG(dAdd, 0.)

!Ajj1 = Amount all-trans-retinoic acid in jejunum compartment 1 (umol)

Cjj1 = Ajj1/Vjj1

dAjj1 = kdd*Add - kjj1*Ajj1 - kabjj1*Cjj1

Ajj1 = INTEG(dAjj1, 0.)

!Ajj2 = Amount all-trans-retinoic acid in jejunum compartment 2 (umol)

Cjj2 = Ajj2/Vjj2

dAjj2 = kjj1*Ajj1 - kjj2*Ajj2 - kabjj2*Cjj2

Ajj2 = INTEG(dAjj2, 0.)

!Ajj3 = Amount all-trans-retinoic acid in jejunum compartment 3 (umol)

Cjj3 = Ajj3/Vjj3

dAjj3 = kjj2*Ajj2 - kjj3*Ajj3 - kabjj3*Cjj3

Ajj3 = INTEG(dAjj3, 0.)

!Ajj4 = Amount all-trans-retinoic acid in jejunum compartment 4 (umol)

Cjj4 = Ajj4/Vjj4

dAjj4 = kjj3*Ajj3 - kjj4*Ajj4 - kabjj4*Cjj4

Ajj4 = INTEG(dAjj4, 0.)

!Ajj5 = Amount all-trans-retinoic acid in jejunum compartment 5 (umol)

Cjj5 = Ajj5/Vjj5

dAjj5 = kjj4*Ajj4 - kjj5*Ajj5 - kabjj5*Cjj5

Ajj5 = INTEG(dAjj5, 0.)

!Ail = Amount all-trans-retinoic acid in ileum compartment (umol)

Cil = Ail/Vil

dAil = kjj5*Ajj5 - kil*Ail - kabil*Cil

Ail = INTEG(dAil, 0.)

!Aco = Amount all-trans-retinoic acid in colon (umol)

dAco = kil*Ail - kfe*Aco

Aco = INTEG(dAco, 0.)

dACco = kil*Ail

ACco = INTEG(dACco, 0.) ! cumulative amount reaching colon

!------

!feces

!AFA = amount all-trans-retinoic acid in feces (umol)

dAFe = kfe*Aco

AFe = INTEG(dAFe, 0.)

!------

!liver compartment

CL = AL/VL

CVL = CL/PL

!AML2C8 = amount all-trans-retinoic acid metabolized in liver by CYP2C8

dAML2C8 = VmaxL2C8*CVL/(KmL2C8 + CVL)

AML2C8 = INTEG(dAML2C8, 0.)

!AML3A4 = amount all-trans-retinoic acid metabolized in liver by CYP3A4

dAML3A4 = VmaxL3A4*CVL/(KmL3A4 + CVL)

AML3A4 = INTEG(dAML3A4, 0.)

!AML3A5 = amount all-trans-retinoic acid metabolized in liver by CYP3A5

dAML3A5 = VmaxL3A5*CVL/(KmL3A5 + CVL)

AML3A5 = INTEG(dAML3A5, 0.)

!AML3A7 = amount all-trans-retinoic acid metabolized in liver by CYP3A7

dAML3A7 = VmaxL3A7*CVL/(KmL3A7 + CVL)

AML3A7 = INTEG(dAML3A7, 0.)

!AML26A1 = amount all-trans-retinoic acid metabolized in liver by CYP26A1

dAML26A1 = VmaxL26A1*CVL/(KmL26A1 + CVL)

AML26A1 = INTEG(dAML26A1, 0.)

!AMLtrag = amountall-trans-retinoicacidmetabolized in liver to all-trans-retinoicacidglucuronide (trag)

dAMLtrag = VmaxLtrag*CVL/(KmLtrag + CVL)

AMLtrag = INTEG(dAMLtrag, 0.)

!AL = Amountall-trans-retinoicacid in livertissue (umol)

dAL = QL*(CB - CVL) + kabdd*Cdd + kabjj1*Cjj1 + kabjj2*Cjj2 + kabjj3*Cjj3 + kabjj4*Cjj4 &

+ kabjj5*Cjj5 + kabil*Cil

- dAML2C8 - dAML3A4 - dAML3A5 - dAML3A7 - dAML26A1 - dAMLtrag

AL = INTEG(dAL, 0.)

!------

!fat compartment

!AF = Amount all-trans-retinoic acid in fat tissue (umol)

CF = AF/VF

CVF = CF/PF

dAF = QF*(CB - CVF)

AF = INTEG(dAF, 0.)

!------

! brain compartment

!ABr = Amount all-trans-retinoic acid in brain tissue (umol)

CBr =ABr/VBr

CVBr = CBr/PBr

dABr = QBr*(CB - CVBr)

ABr = INTEG(dABr, 0.)

!------

! heart compartment

!AH = Amount all-trans-retinoic acid in heart tissue (umol)

CH = AH/VH

CVH = CH/PH

dAH = QH*(CB - CVH)

AH = INTEG(dAH, 0.)

!------

! kidney compartment

!AK = Amount all-trans-retinoic acid in kidney tissue (umol)

CK = AK/VK

CVK = CK/PK

dAK = QK*(CB - CVK)

AK = INTEG(dAK, 0.)

!------

! lung compartment

!ALu = Amount all-trans-retinoic acid in lung tissue (umol)

CLu =ALu/VLu

CVLu = CLu/PLu

dALu = QLu*(CB - CVLu)

ALu = INTEG(dALu, 0.)

!------

! muscle compartment

!AM = Amount all-trans-retinoic acid in muscle tissue (umol)

CM = AM/VM

CVM = CM/PM

dAM = QM*(CB - CVM)

AM = INTEG(dAM, 0.)

!------

!tissue compartment rest of body

!AR = Amount all-trans-retinoic acid in rest of body (umol)

CR = AR/VR

CVR = CR/PR

dAR = QR*(CB - CVR)

AR = INTEG(dAR, 0.)

!------

! blood compartment

!AB = Amount all-trans-retinoic acid in blood (umol)

CB = AB/VB

CP = CB/Rbp

dAB = QF*CVF + QL*CVL + QBr*CVBr + QH*CVH + QK*CVK + QLu*CVLu

+ QM*CVM + QR*CVR - QC*CB

AB = INTEG(dAB, AB0)

AUC = INTEG(CB, 0.)

!======

!Massbalancecalculations

!======

Total = ODOSE + IVDOSE

MB = Ast + Add + Ajj1 + Ajj2 + Ajj3 + Ajj4 + Ajj5 + Ail + Aco + AFe

+ AL + AML2C8 + AML3A4 + AML3A5 + AML3A7 + AML26A1 + AMLtrag

+ AF + ABr + AH + AK + ALu + AM + AR + AB

Emet = AML2C8 + AML3A4 + AML3A5 + AML3A7 + AML26A1 + AMLtrag

Agi =Ast + Add + Ajj1 + Ajj2 + Ajj3 + Ajj4 + Ajj5 + Ail

Efe =Aco + AFe

END ! DERIVATIVE

! Add discrete events here as needed

! DISCRETE

! END

! code that is executed once at each communication interval goes here

CONSTANT TSTOP = 24.0

TERMT (T .GE. TSTOP, 'checked on communication interval: REACHED TSTOP')

END ! DYNAMIC

TERMINAL

! code that is executed once at the end of a simulation run goes here

END ! TERMINAL

END ! PROGRAM