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 WI TH 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

!

- Physiologi cal 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 perfu sed

!

- 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.CS L 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 ti ssue, 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 Septe mber

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 outp ut (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 (fractio n 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 ! Li ver

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

T SA = 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

Q SKvC = 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 Weig hts

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

CONSTAN T 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 ! Vm axc/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)

! In itialize 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

c onstant 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

-- > 0AH20 = (DENSITY+1.0

- CONCL)*VLIQ0 ! ... and add it to

H20.

! Note, for application of 100% N MP, 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 10 0% 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. !Conv ert 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 * QCInitQSkl = 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 = (V SlwC * 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 = IC Mam * 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 absorptionODOSE1= 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'

CONSTA NT 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+REPT M

- 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 = 0.0END

discrete OND2

DZONE=1.0

SCHEDULE OND2.AT.(T+24.0)

SCHEDULE OFFD.A T.(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 mam mary 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*ex p(

- 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 = QCIn it + (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

- R AMet1

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 DOSI NG

(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 (Day swk=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 fro m 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

com partment

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 vap or);

! "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) + R ADVv ! 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 Slowl y 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 / VU tr

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)

! Am ount 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(RA 5H, 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 Pro gram