PROGRAM NMPhumPG.ACSL

!PBPK MODEL FOR N-METHYL PYRROLIDONE in pregnant women

!T.S. POET,P HINDERLITER. CHEMICAL DOSIMETRY GROUP, PNNL, RICHLAND, WA

!First Created 8.8.08

!FINAL REPORT FROM INITIAL rat MODEL DEVELOPMENT SUBMITTED 9.02

!MODEL CONFIGURED FOR INHALATION (OPEN, WHOLE BODY/NOSE ONLY)

! IV, ORAL, DERMAL, AND IP ROUTES OF ADMINISTRATION. 

!MODEL TRACKS DISPOSITION OF NMP AND 5-HNMP. 

!ASSUMPTIONS: 

! (1) FLOW-LIMITED (ALL COMPARTMENTS) 

! (2) METABOLISM OF NMP BY A sat PATHWAY TO FORM 5HNP

! (3) METABOLISM OF HNP BY SATURABLE PATHWAY TO ETC. 

! (5) METABOLISM OCCURS ONLY IN THE LIVER 

! (6) TISSUE:BLOOD PART. COEFF. RAT = HUMAN = KRISHNAN EQN 

! updated in cmd file to measured in-house

! (7) 5HNP ELIMIN FROM MIXED VENOUS - 1ST ORDER

! THIS DIFFERS FROM 02: URINE BY *GFR CLEARANCE FROM KIDNEY

! METAB RATE CONST. FROM REPORT - UPDATED WITH LIT VALUES in cmd file

! Other parameters changed nominally to harmonize with fetal IPA model 

of 

! Gentry et al. Regu Tox Pharm 36:51-68, 2002

! Gentry model notes:

! -Coding for pregnancy is from MeHgFat.CSL with some minor changes

! -Physiological parameters are from MeHgFat.CSL (ajusted as needed)

! -Non-pregnant mammary tissue and uterine volume is from ICRP

! -Non-pregnant mammary tissue and uterine blood flows are based on the

! - ratios of mammary and uterine tissue volumes to rapidly perfused

! - tissue volume and blood flow to rapidly perfused tissue where rapidly

! - perfused tissue includes liver, lung, etc.

! - ((VMamC/VRapC)*QRapC) and ((VUtrC/VRapC)*QRapC)

! -Data used to fit curve for growing rapidly perfused tissue in

! - MeHgFat.CSL was refit separately to fit curves for growing uterus

! - and mammary tissue in this model

! -Body weight and cardiac output are calculated as the initial values

! - plus the change in the growing compartments

! -Increase in blood flow to fat, mammary tissue, and uterus are modeled

! - as being proportional to the increase in volume in those compartments

! - based on the data in Thoresen and Wesche, 1988 (uterus and mammary

! - tissue)

!

! Further updates by Paul Schlosser, US EPA in August 2013 and September 

2014

INITIAL

table reslvl, 1, 1441 / 1441*0.0, 1441*0.0 /

! Human Total Pulmonary Ventilation Rate (L/hr for 1 kg animal)

 CONSTANT QPC = 27.75
! Human Blood Flows (fraction of cardiac output)

 CONSTANT QCC = 12.9 ! Cardiac output (L/hr for 1 kg animal)

 CONSTANT QFatC = 0.052 ! Fat (non-pregnant female)

 CONSTANT QLivC = 0.227 ! Liver

 CONSTANT QMamC = 0.027 ! Mammary tissue (non-pregnant female)

 CONSTANT QRapC = 0.325 ! Rapidly perfused

CONSTANT QSkC = 0.058 ! Skin

 CONSTANT QUtrC = 0.0062 ! Uterus (non-pregnant female)

! Permeability-Area Product (L/hr)

 CONSTANT PAFC = 0.01 ! Diffusion on fetal side of placenta 

from Gentry

! Human Tissue Volumes (fraction of body weight)

 CONSTANT BWInit = 67.8 ! Pre-pregnancy body weight (kg)

 CONSTANT VAlvC = 0.0079 ! Alveolar blood

 CONSTANT VBLC=0.06

 CONSTANT VFatC = 0.273 ! Fat (non-pregnant female)

 CONSTANT VLivC = 0.026 ! Liver

 CONSTANT VMamC = 0.0062 ! Mammary tissue (non-pregnant female)

 CONSTANT VRapC = 0.1044 ! Rapidly perfused

 !CONSTANT VSlwC ! Slowly perfused is calculated 

below

 CONSTANT VUtrC = 0.0014 ! Uterus (non-pregnant female)

 CONSTANT VSKC=0.19

! Human Dermal Exposure Parameters

 CONSTANT P = 0.0016 ! Permeability constant (Kp) (cm/hr)

 CONSTANT PV=31.0 ! PERMEABILITYT 

CONSTANT (CM/HR) FOR VAPOR

 

 

!FOR PARENT MODEL, SKIN COMPARTMENT IS ONLY DEFINED AS DOSED SKIN

 CONSTANT SAl = 0.01 !SURFACE AREA EXPOSED to liquid, 

SQ.CM

 CONSTANT SAvc = 0.25 !fraction SURFACE AREA EXPOSED to 

gas/vapor, SQ.CM

 CONSTANT HT=170.0 !height (or length) of reference man

 TSA = 71.81*(BWinit**0.425)*(HT**0.725) !for humans, DuBois and 

DuBois, 1916, as reported in Reference Man

SAv = SAVC*TSA ! SURFACE AREA EXPOSED to gas/vapor, 

SQ.CM

 VSKlC = VSKC*SAl/TSA

 QSKlC = QSKC*SAl/TSA

 VSKvC = VSKC*SAv/TSA

 QSKvC = QSKC*SAv/TSA

CONSTANT FAD = 0.0 !FRACTION ABSORBED - FROM BADER ET AL, CALCULATE FROM 

AMNT REMAINING ON GAUZE

CONSTANT PVL=0.0

 

 ! Slowly perfused (defined as balance of tissues and flows)
 VSlwC = 0.91 - ( VFatC + VLivC + VMamC + VRapC + VUtrC + VSKvC + 

VSKlC)

 ! NOTE: 0.91 IS APPROX WHOLE BODY LESS BONE

 VSLwC5=0.91 - (VFatC + VLivC + VRapC) 

 QSlwC = 1.0 - (QFatC + QLivC + QMamC + QRapC + QUtrC + QSKvC + QSKlC)

 QSlwC5 = 1.0 - (QFatC + QLivC + QRapC)

 

! Molecular Weights

 CONSTANT MW=99.13 !MOL. WT. NMP, MG/MMOL

CONSTANT MW1= 116.14 !MOL. WT. 5-HNP, MG/MMOL

 Stoch = MW1/MW

! Human NMP/Blood Partition Coefficients

!EXPERIMENTALLY MEASURED RATVALUES

 CONSTANT PB = 450.0 ! Blood/air

 CONSTANT PFat = 0.61 ! Fat

 CONSTANT PLiv = 1.00 ! Liver

 CONSTANT PMam = 1.0 ! Mammary tissue, estimated from liver

 CONSTANT PPla = 0.31 ! Placenta

 CONSTANT PRap = 1.0 ! Rapidly perfused tissue, liver

 CONSTANT PSlw = 0.30 ! Slowly perfused tissue, muscle

 CONSTANT PUtr = 0.34 ! Uterus

 CONSTANT PSKA = 44.5 ! use (blood/air)*(rat 

skin:liquid)/(human blood:liquid)

 CONSTANT PSKL = 0.42 ! MEASURED SKIN;LIQUID (rat)

constant pskb = 0.099 ! (rat skin:liquid)/(human 

blood:liquid)

 CONSTANT PLU= 0.1 ! LUNG:BLOOD

 

!METABOLIC RATE CONSTANTS

!**THESE ARE FROM PAYAN ET AL

 !NMP TO 5HNP

CONSTANT Af1 = 0.0112 ! AFFINITY CONSTANT, l/MG

CONSTANT VK1C = 0.4663 ! Vmaxc/Km, 1/(hr * BW^0.75 )

! Human 5HNMP volume of distribution

CONSTANT VOD5Hc = 0.3 ! VOLUME-OF-DISTRIBUTION

VOD5H = VOD5Hc*BWinit

 !No fetal compartment for metabolite, NMP is considered the active 

moiety 

!5HNP TO OTHER METABS

 ! CONSTANT KM2=22.8 !MICHAELIS CONSTANT, MG/L

 ! CONSTANT VMAX2C=1.0 !MAX. ENZ. ACT., MG/HR/L

 CONSTANT VK2C=0.0326 ! VMAX2C/KM2, since clearance ~ liner 

1/(hr*kg^0.75)

! Human Uptake and Clearance Parameters

 !URINARY ELIMINATION OF 5-HNMP - CLEARED FROM BLOOD

 !note first order rate commented out, saturable fits better

 CONSTANT KAS=5.0

 CONSTANT KME=3.83 !First-order constant for 5HNMP in urine 

(L/hr)
 CONSTANT KUMNE=0.182 !First-order CONSTANT FOR NMP IN 

URINE (L/hr)

 

! Initialize Human Concentrations in Tissues (mg/L)

 CONSTANT ICArt = 0.0 ! Blood

 CONSTANT ICFat = 0.0 ! Fat

 CONSTANT ICLiv = 0.0 ! Liver

 CONSTANT ICRap = 0.0 ! Rapidly perfused

 CONSTANT ICSkn = 0.0 ! Skin

 CONSTANT ICSlw = 0.0 ! Slowly perfused

 ICMam = ICSlw ! Mammary tissue

 ICUtr = ICRap ! Uterus

! Dosing Parameters

 CONSTANT Concppm = 0.0 ! Inhaled concentration (ppm)

 CONSTANT CONCMGM = 0.0 ! Inhaled concentration 

(mg/m3)

 CONSTANT IVDose = 0.0 ! IV dose (mg/kg)

 CONSTANT PDose = 0.0 ! Oral dose (mg/kg)

constant PDose2=0.0

constant PDose3=0.0

 CONSTANT PDrink = 0.0 ! Drinking water dose (mg/kg/day)

 CONSTANT TChng = 24.0 ! Length inh. exposure or IV inj.(hrs)

 CONSTANT DaysWk = 5.0 ! Number of exposure days per week

 CONSTANT TMax = 24.0 ! Maximum time for exposures

CONSTANT s2=0.0

!INHALATION ON

CONSTANT p2=3.0

!INHALATION EXPOSURE

CONSTANT S3=3.16 !INHALTION 

RESUME (HANOVER STUDY)

CONSTANT P3=3.0

!SECOND DAILY EXPOSURE PERIOD

constant on3=1.0 ! Set to zero to turn off 2nd daily pulse;

constant fullweek=168.0 ! hrs in a fullweek

hrsweek=24.0*DaysWk ! hrs/week in workplace

! STARTDS IS ADDED TO TCHNG TO ALLOW FOR DOSING THAT DOES NOT START AT 

T=0

!INITIAL EXPOSURE CONDITIONS

!DERMAL

 CONSTANT CONCL = 0.0 !CONC OF NMP IN LIQUID, MG/L

constant srate = 0.0 ! mg/hr delivered to 

skin by spray application

 CONSTANT VLIQ0 = 1.0e-99 !INITIAL VOLUME APPLIED, L

 CONSTANT DENSITY=1.02e6 ! Density (mg/L) @ 40C, ~ skin 

temperature

 CONSTANT RESID=0.0 !AMOUNT STICKING TO EXPOSURE 

SYSTEM, MG

constant BRUSH=0.0 ! Set to 1.0 for 

brush/liquid exposure

 DDN = (CONCL - 1.0)*VLIQ0*FAD ! Subtract 1 mg/L, ~ 1 ppm, from 

initial conc. to avoid VLIQ --> 0
AH20 = (DENSITY+1.0-CONCL)*VLIQ0 ! ... and add it to 

H20.

! Note, for application of 100% NMP, it is not possible for CSURF to drop 

below 100%. 

! 100% NMP is not diluted in anything, so the "solution" can't become 

less dilute. 

! The volume (VLIQ) would actually decrease until it's all absorbed. 

! Unless the experiment runs long enough for 100% absorption, treat VLIQ 

as

! extremely large, ~ 10^9, for 100% NMP.

! But check that you don't predict more absorption than was actually 

applied!

 !IN VITRO HUMAN VAN DYK ET AL. AIHA J 56: 651-660

 !START WITH SMALL SA SO VSKE IS NON-ZERO (USED IN DENOMINATOR OF 

CSK CALCULATION)

 ! Exposure Conditions Based on User Defined Initial Amounts of Chemical 

(mg)

 IF (concppm.EQ.0.0) THEN

 concmg=concmgm/1000.0 !CONCERT MG/M3 

to mg/L

 ELSE

 CONCmg = CONCppm*MW/24451. !Convert ppm to mg/Liter!

 ENDIF

!CONSTANT CONCMG=0

!HANNOVER STUDY UNIT MG/M3 SO CONCMG /1000(l/M3) 

CONSTANT DOSEINTERVAL=24.0 !TIME BETWEEN DAILY 

DOSES

 

! Simulation Control Parameters

 CONSTANT StartDs = 0.0 ! Time first dose is given (hrs)

 CONSTANT TStop = 6480.0 ! Run simulation for about 9 months

 CONSTANT CIntC = 0.1

CONSTANT GDstart = 0.0 ! Gestation day on which 

simulation starts

! Scaled Human Pulmonary Ventilation Rate (L/hr)

 QP = QPC * (BWInit**0.75)

 QAlv = 0.67 * QP

! Scaled Human Blood Flows (L/hr)

 QCInit = QCC * (BWInit**0.75)

 QFatI = QFatC * QCInit

 QLiv = QLivC * QCInit

 QMamI = QMamC * QCInit

QPlaI = 58.5 * VPlaI ! value for 'days'=0 per calculation 

below

 QRap = QRapC * QCInit

 QSlw = (QSlwC * QCInit) - QPlaI

 QUtrI = QUtrC * QCInit
 QSkl = QSKlC * QCInit

 QSkv = QSKvC * QCInit

! Scaled Human Tissue Volumes (L)

 VAlv = VAlvC * BWInit

 VFatI = BWInit*(VFatC+(0.09*exp(-12.90995862*exp(-

0.000797*24.0*GDstart))))

 VFetI = 3.50 * (exp(-16.081*exp(-5.67e-4*24.0*GDstart))+ exp(-

140.178*exp(-7.01e-4*24.0*GDstart)))

 VMamI = BWInit*(VMamC+(0.0065*exp(-7.444868477*exp(-

0.000678*24.0*GDstart))))

 VPlaI = 0.85*exp(-9.434*exp(-5.23e-4*24.0*GDstart))

 VUtrI = BWInit*(VUtrC+(0.02*exp(-4.715669973*exp(-

0.000376*24.0*GDstart))))

 VLiv = VLivC * BWInit

 VRap = VRapC * BWInit

 VSKl = VSKlC * BWinit

 VSKv = VSKvC * BWinit

 VBL=VBLC * BWINIT

 VSlw = (VSlwC * BWInit)

! Scaled Human Metabolism Parameters

VK1 = VK1C * (BWInit**0.75)

 VK2 = VK2C * (BWInit**0.75)

! Initialize Human NMP Amounts in Tissues

 IAArt = ICArt * VAlv

 IAFat = ICFat * VFatI

 IALiv = ICLiv * VLiv

 IAMam = ICMam * VMamI

 IARap = ICRap * VRap

 IASkl = ICSkn * VSKl

 IASkv = ICSkn * VSKv

 IASlw = ICSlw * VSlw

 IAUtr = ICUtr * VUtrI

 InitTot = IAArt + IAFat + IALiv + IAMam + IARap + IASkl + IASkv + 

IASlw + IAUtr

! Initialize Starting Values

 BW = BWInit

 Drink = (PDrink * BW) / 24.0 ! Drinking water dose (mg/hr)

 CINT = CIntC

 IV = 0.0

 DayExp = 1.0

 CInh = 0.0

 CONSTANT FRACIN = 0.97 !FRACTIONAL UPTAKE OF NMP BY INHAL,START 

AT 65%

 !of alveolar - as in Akesson et 

al 1997

 CONSTANT FRACOR = 1.0 !FRACTION ABSORBED ORALLY, INITALLY 100%

! Convert oral dose from ug/kg to umoles 

! Modify dose to account for fractional absorption 
ODOSE1= PDOSE * BW * FRACOR ! umoles

ODOSE2= PDOSE2* BW * FRACOR ! umoles

ODOSE3= PDOSE3* BW * FRACOR ! umoles

CONSTANT TIME=0.0

CONSTANT TIME1 = 0.0 ! !'daily rat expo (hr)' 

CONSTANT TIME2 = 4.0 ! !'SECOND DAILY EXPOSURE (hr)' 

CONSTANT TIME3 = 4.0 ! !'THIRD DAILY DOSE'

CONSTANT REPTM=720.0 ! CHANGE TO 24 FOR DAILY DOSING

SCHEDULE DOSE1 .AT. TIME1

DZONE = 1.0 ! Start with exposure on

schedule offd.at.p2

schedule OND2.at.24.0

if (ON3) schedule OND3.at.s3

END ! End of Initial

DYNAMIC

 ALGORITHM IALG = 2 ! Gear stiff method

DISCRETE DOSE1

ODOSE = ODOSE+ODOSE1

SCHEDULE DOSE2 .AT. (TIME+TIME2)

END

DISCRETE DOSE2

ODOSE = ODOSE+ODOSE2

SCHEDULE DOSE3 .AT. (TIME+TIME3)

END

DISCRETE DOSE3

ODOSE = ODOSE+ODOSE3

SCHEDULE DOSE1 .AT. (TIME+REPTM-TIME2-TIME3)

END

DISCRETE DoseOn ! Start dosing

 INTERVAL DoseInt = 24.0 ! Interval to repeat dosing

 SCHEDULE DoseOff .AT. T + TChng

 IF ((T.GE.StartDs) .AND. (T.LT.TMax)) THEN

IF (T.LE.(StartDs+TChng)) THEN

IF (IVDose.GT.0.0) CINT = MIN(CIntC, (TChng/10.0))

 IV = (IVDose*BW) / TChng ! Rate of intravenous dosing (mg/hr)

ENDIF

ENDIF

END ! DoseOn

DISCRETE DoseOff

 CInh = 0.0

 CINT = CIntC

 IV = 0.0
END

discrete OND2

DZONE=1.0

SCHEDULE OND2.AT.(T+24.0)

SCHEDULE OFFD.AT.(T+P2)

END

discrete OND3

DZONE=1.0

SCHEDULE OND3.AT.(T+24.0)

SCHEDULE OFFD.AT.(T+P3)

END

!EXPOSURE CONTROL

DISCRETE OFFD

DZONE=0.0 !TURN OFF DERMAL

END

DERIVATIVE

 Hours = T

 Minutes = T * 60.0

 Days = T / 24.0 + GDstart

Gtime = T + GDstart*24.0

! Volume of human fat (L)

 VFat = BWInit*(VFatC+(0.09*exp(-12.90995862*exp(-0.000797*Gtime))))

! Volume of human fetus (L)

 VFet = 3.50 * (exp(-16.081*exp(-5.67e-4*Gtime))+ exp(-140.178*exp(-

7.01e-4*Gtime)))

! Volume of human mammary tissue (L)

 VMam = BWInit*(VMamC+(0.0065*exp(-7.444868477*exp(-

0.000678*Gtime))))

! Volume of human placenta (L)

 VPla = 0.85*exp(-9.434*exp(-5.23e-4*Gtime))

! Volume of human uterus (L)

 VUtr = BWInit*(VUtrC+(0.02*exp(-4.715669973*exp(-0.000376*Gtime))))

! Increase in human body weight (kg)

 BW = BWInit + (VFat - VFatI) + VFet + (VMam - VMamI) + VPla + 

(VUtr - VUtrI)

! Scaled human alveolar ventilation (L/hr)

 QP = QPC * (BW**0.75)

 QAlv = 0.67 * QP

! Increase in human blood flows (L/hr)

 QFat = QFatI * (VFat / VFatI)

 QMam = QMamI * (VMam / VMamI)

 QUtr = QUtrI * (VUtr / VUtrI)
! Human Blood flow to placenta (L/hr)

 QPla = 58.5 * VPla

! Increased human cardiac output (L/hr)

 QC = QCInit + (QFat - QFatI) + (QMam - QMamI) + (QPla - QPlaI) + 

(QUtr - QUtrI) 

QSlw5 = Qc - (QFat + QLiv + QRap)

VSlw5 = BW - (VFat + VLiv + VRap)

! Scaled permeability-area product

 PAF = PAFC * (VFet**0.75)

! ------------------ HUMAN NMP MODEL -------------------------

! Amount Exhaled (mg)

 RAExh = QAlv * CAlv

 AExh = INTEG(RAExh, 0.0)

CI = concmg*czone + RESLVL(T)

! for a 5 day/wk exposure, change first pulse to pulse(0,7*24,5*24)

! for daily, pulse(0,1e6,24)

TORAL= ODOSE1 - AO !AMT ABSORBED ORALLY, MG!

RSTOM = -KAS*AO

RAO = KaS*AO ! Change in stomach (umole/hr) 

AO=ODOSE1+INTEG(Rstom,0.0) ! Amt in stomach (umole) 

! Amount in Fat (mg)

 RAFat = QFat * (CArt - CVFat)

 AFat = INTEG(RAFat, IAFat)

 CFat = AFat / VFat

 CVFat = CFat / PFat

! Amount in Fetus (mg)

 RAFet = PAF * (CPla - CFet)

 AFet = INTEG(RAFet, 0.0)

 CFet = AFet / VFet

 AUCCFet = INTEG(CFet, 0.0)

 

! Amount in Liver (mg)

 RALiv = (QLiv * (CArt - CVLiv)) + RAO + Drink - RAMet1

 ALiv = INTEG(RALiv, IALiv)

 CLiv = ALiv / VLiv

 CVLiv = CLiv / PLiv

! Amount Metabolised in Liver -- Saturable (mg)

 RAMet1 = VK1 * CVLiv / (1 + af1*CVLiv)

 AMet1 = INTEG(RAMet1, 0.0)

! Amount in Mammary Tissue (mg)

 RAMam = QMam * (CArt - CVMam)

 AMam = INTEG(RAMam, IAMam)
 CMam = AMam / VMam

 CVMam = CMam / PMam

 

! Amount in Placenta (mg)

 RAPla = (QPla * (CArt - CVPla)) + (PAF * (CFet - CPla))

 APla = INTEG(RAPla, 0.0)

 CPla = APla / VPla

 CVPla = CPla / PPla

 

! Amount in Rapidly Perfused Tissue (mg)

 RARap = QRap * (CArt - CVRap)

 ARap = INTEG(RARap, IARap)

 CRap = ARap / VRap

 CVRap = CRap / PRap

!ASKl = AMOUNT NMP IN liquid-exposed SKIN TISSUES (MG) AND DERMAL DOSING 

(from vapor)

! Liquid exposure when czone = 1, otherwise czone = 0. CI = air 

concentration

czone = pulse(0.0,fullweek,hrsweek)*DZONE

! for a 5 day/wk exposure, use fullweek=7*24, hrsweek=5*24 (Dayswk=5)

! for a single day, fullweek=1e16, hrsweek=24 (Dayswk=1)

RADL = (PVL*SAL/1000.0)*(CSURF - (CSKL/PSKL))*czone*BRUSH

 ! Net rate of delivery to "L" skin from liquid, when liquid is there

ADLL = integ(RADL, 0.0)

RADVL = (PV*SAL/1000.0)*(CI - (CSKL/PSKA))*(1.0-Czone)

! Net rate of delivery to "L" skin from air, when liquid not present

ADVL = integ(RADVL, 0.0)

ASURF = INTEG(-RADL, DDN) ! Aount in liquid. DDN is the initial amount.

VLIQ = (AH20 + ASURF)/DENSITY

CSURF = ASURF/VLIQ

RASKL = QSKL*(CArt - CvSKL) + RADL + RADVL ! Rate of change in "L" skin 

compartment

ASKL = INTEG(RASKL, 0.0) ! Amount in "L" skin

CSKL = ASKL/VSKL ! Concentration in "L" skin

CvSKL = CSKL/PSKB ! Concentration in venous blood exiting 

"L" skin

!ASKv = AMOUNT NMP IN vapor-exposed SKIN TISSUES (MG) AND DERMAL DOSING 

(from vapor);

! "SKv" (vapor-only-exposed) skin compartment. CI = air concentration

RADVv = (PV*SAv/1000.0)*(CI - (CSKv/PSKA)) ! Net rate of transfer from 

air to skin

 ADVv = INTEG(RADVv,0.0) !'AMT NMP ABSORBED DERMAL,MG'

RASKv = QSKv*(CArt - CvSKv) + RADVv ! Rate of change in "V" skin

ASKv = INTEG(RASKv, 0.0) ! Amount in "V" skin

CSKv = ASKv/VSKv ! Concentration in "V" skin

CvSKv = CSKv/PSKb ! Concentration in venous blood 

exiting "V" skin
! Amount in Slowly Perfused Tissue (mg)

 RASlw = QSlw * (CArt - CVSlw)

 ASlw = INTEG(RASlw, IASlw)

 CSlw = ASlw / VSlw

 CVSlw = CSlw / PSlw

! Amount in Uterus (mg)

 RAUtr = QUtr * (CArt - CVUtr)

 AUtr = INTEG(RAUtr, IAUtr)

 CUtr = AUtr / VUtr

 CVUtr = CUtr / PUtr

! BLOOD VENOUS ARTERIAL (c) 

CVEN=(QFAT*CVFat + QLIV*CVLiv + QMAM*CVMam + QPLA*CVPla + QRap*CVRap + 

QSlw*CVSlw &

 + QUtr*CVUtr + QSKV*CVSKv + QSKL*CVSKL + IV) / QC

ivtot=INTEG(IV, 0.0)

! Amount in Arterial Blood (mg)

RAINH = QAlv*(CI*FRACIN - CAlv)

 RABld = RAINH + QC*(CVen-CArt) - RAUNP

INhaltot = INTEG(RAINH, 0.0)

 ABld = INTEG(RABld, IAArt)

 CArt = ABld / VBL

 CAlv = CArt / PB

 CAlvPPM = CAlv * 24450.0 / MW

 AUCCBld = INTEG(CArt, 0.0)

! Amount in Urine (mg)

 RAUNP = KUMNE*CART !FIRST ORDER RATE OF LOSS (URINE

AUNP = INTEG(RAUNP,0.0)

! -------------------- HUMAN 5HNMP MODEL --------------------------

! Amount in body (mg)

 RA5H = (RAMet1*STOCH) - RAMetM1 - RAUHP

 A5H = INTEG(RA5H, 0.0)

 Cven1 = A5H / VOD5H

! Amount Metabolised [in Liver] -- Saturable (mg)

RAMetM1 = VK2*Cven1

 AMetM1 = INTEG(RAMetM1, 0.0)

! Amount in Urine (mg)

 RAUHP = KME*Cven1

AUHP = INTEG(RAUHP,0.0)

! ----------------- CHECK MASS BALANCE ------------------------------

 INTOT=INTEG((QAlv*CI*FRACIN), 0.0)

 TDose = INTOT + AO + InitTot+TORAL+ADLL+ADVL+ADvV 

 NMPTOT = ABld + AFat + AFet + ALiv + AMam + APla + ARap + ASkl + ASkv 

+ ASlw + AUtr + AExh + AUnp + AMET1

 MassBal = TDose/(NMPTOT+0.000000000001)
 

TERMT(T.GT.TSTOP, 'Simulation Finished')

END ! End of Derivative

TERMINAL

 DAUCCBld = AUCCBld * 24.0 / TStop

 DAUCCFet = AUCCFet * 24.0 / TStop

END

END ! End of Dynamic

END ! End of Program