species extrapolation with pbpk models kannan krishnan université de montréal, canada
TRANSCRIPT
Species extrapolation with PBPK models
Kannan KrishnanUniversité de Montréal, Canada
Outline
Introduction Rat-Human extrapolation
Single chemicals Mixtures QSARs
Rat-Fish extrapolation PBPK modeling QSARs
Conclusions
PBPK Models and Interspecies Extrapolation
Adipose tissue
Richly perfused tissues
Liver
Poorly perfusedtissues
Lungs
Inhaled Exhaled
STRUCTURE INPUT
PARAMETERS
SIMULATIONS
PBPKProgram
RAT HUMAN
RAT
HUMAN
T
C
T
C
or
Functional Representation
Amount
tdAInput Output
dt
Blood flow to tissue, volume, partition coefficient
Functional RepresentationMetabolic Clearance
CK
CV
m max
Vmax = maximum velocity of metabolismKm = Michaelis-Menten constantC = concentration of chemical
Metabolizing enzyme, its levels, tissue volume
ExtrapolationExtrapolation
INVARIANT:INVARIANT:Species Species SPECIFIC:SPECIFIC:
Vmaxc
Km
Tissue:air PC
Blood:air PC
Flows
Volumes
[P-450]
Interspecies extrapolation of PK of chemicalsInterspecies extrapolation of PK of chemicals
Species Species SPECIFIC:SPECIFIC:
Blood:air PC
Flows
Volumes
[P-450]
Mixture PBPK Models and Interspecies Extrapolation
STRUCTUREINPUT
PARAMETERS
SIMULATIONS
ComputerComputerProgramProgram
RAT HUMAN
RAT
HUMAN
T
C
T
C
or
Arterial blood
FatFat
LungsLungs
Poorly perfusedtissues
Poorly perfusedtissues
Richly perfusedtissues
Richly perfusedtissues
LiverLiver
metabolism
Venous blood
A B C D E A B C D E
QSARs for PBPK Parameters
Fragment constant approach Ppbpk = nf·Cf
Multilinear regression (SPSS®) 46 VOCs, Fragments: CH3, CH2, CH, C, C=C,
H, Cl, Br, F, B-ring, 2 E1 substrates Cross-validation, external validation
Structure Input@Chemical
Exposure Condition
Yellow Indicates User Input
QSAR/PBPK model – Ethyl benzene
QSAR/PBPK model:Dichloromethane
Conceptual Representation
Inspired chemicalExpired chemical
Ven
ous
Blo
od
Arterial B
lood
Rest of Body
Kidneys
Muscle
Liver
Gills
Effective respiratory volume (Qv) Cex Cin
Cardiac ouput (Qc) Ca Cv
Gills
Pulmonary ventilation (Qv) Cex Cin
Cardiac output (Qc) Cv Ca
Lungs
Ventilation limited exchange : Pb = Cv/ Cex
Blood flow limited exchange : Pb = Ca/ Cin
Partition Coefficients
Tissue:water PCs Determinants of bioconcentration factors May vary between species (rat vs fish), if the
composition of tissues change from one species to another
Tissue components: lipids, water, proteins Lipids (neutral, phospho) + water
Tissue composition based Computation of PCs
ptwtptnte: oe:t F 0.7 F F 0.3 F P P
Po:e = n-octanol:env partition coefficientPt:e = tissue:env partition coefficientFnt = volume fraction of neutral lipids in tissueFpt = volume fraction of phospholipids in tissueFwt = volume fraction of water in tissue
Interspecies differences in mechanistic determinants (PCs)
Tissue and species
Neutral lipid eqvt
Water eqvt
Muscle
Rat 0.0117 0.7471
Human 0.0378 0.7573
Catfish 0.0041 0.7960
FHM 0.0194 0.8116
Trout 0.0244 0.7746
Interspecies extrapolation of tissue:air partition coefficients (Humans)
Log fat:air mecaniste
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
-0.5 0.5 1.5 2.5 3.5 4.5
Log EXPTL
Log
PR
ED
Log liver:air mecaniste
y = 0.9721x
R2 = 0.8686
-0.5
0
0.5
1
1.5
2
2.5
3
-0.5 0 0.5 1 1.5 2 2.5 3
Log EXPTL
Log
PR
ED
Log muscle:air mecaniste
y = 0.8858x
R2 = 0.814
-0.5
0
0.5
1
1.5
2
2.5
-0.5 0 0.5 1 1.5 2 2.5
Log EXPTL
Lo
g P
RE
D
R2 = 0.969Y = 0.973X
R2 = 0.993Y = 0.992X
R2 = 0.933Y = 0.886X
Interspecies extrapolation of tissue:air partition coefficients (Fish)
Channel catfish
y = 1.4883x
R2 = 0.9977
1
10
100
1000
10000
100000
1 10 100 1000 10000
Exptl PC
Pre
d P
C
Fathead minnow
y = 2.5499x
R2 = 0.9992
1
10
100
1000
10000
100000
1 10 100 1000 10000
Exptl PC
Pre
d P
C
Rainbow trout
y = 1.343x
R2 = 0.9981
1
10
100
1000
10000
100000
1 10 100 1000 10000
Exptl PC
Pre
d P
C
Application (chloroethane)
Log Poa = 0.373 +0.433 +0.785 = 1.6Log Pwa = -0.031 -0.225 +0.471 = 0.215
*101.6 + *100.215 = 2.87 Rat Pla
Trout Pla
0.0425 0.7176
*101.6 + *100.215 = 2.29 0.0261 0.7649
C C
H
H
H
H
H
CL
Magnitude of Interspecies Differences in Tissue:Water PCs
)BF 0.7 (BF )BF 0.3 (BF P
)AF 0.7 (AF )AF 0.3 (AF P A/B P
ptwtptntw: o
ptwtptntw: ow: t
Po :w = n-octanol:water partition coefficientPt :a = tissue:water partition coefficientFnt = volume fraction of neutral lipids in tissueFpt = volume fraction of phospholipids in tissueFwt = volume fraction of water in tissueA & B = two differents species
Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,0
0,5
1,0
1,5
2,0
2,5
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
b:w
rat
io
trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka
Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,0
0,5
1,0
1,5
2,0
2,5
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
b:w
rat
io
trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka
Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,0
0,5
1,0
1,5
2,0
2,5
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
b:w
rat
io
trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka
Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,0
0,5
1,0
1,5
2,0
2,5
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
b:w
rat
io
trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka
Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,0
0,5
1,0
1,5
2,0
2,5
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
b:w
rat
io
trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka
Calculated magnitude of interspecies differences in blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,0
0,5
1,0
1,5
2,0
2,5
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
b:w
rat
io
trout/catfish medaka/catfishtrout/medaka FHM/catfishtrout/FHM FHM/medaka
Calculated magnitude of interspecies differences in liver:water (Pl:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,00,51,01,52,02,53,03,54,04,55,0
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
l:w
rat
io trout/catfishmedaka/catfishtrout/medaka
Calculated magnitude of interspecies differences in liver:water (Pl:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,00,51,01,52,02,53,03,54,04,55,0
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
l:w
rat
io trout/catfishmedaka/catfishtrout/medaka
Calculated magnitude of interspecies differences in liver:water (Pl:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
0,00,51,01,52,02,53,03,54,04,55,0
0,001 0,01 0,1 1 10 100 1000 10000
Po:w
Inte
rsp
ecie
s P
l:w
rat
io trout/catfishmedaka/catfishtrout/medaka
Interspecies extrapolation of metabolism constants Vmax in one species Allometrically scale to another species Assume Km to be species invariant Worked well for CYP2E1 subtrates
Structure-Metabolic Constants Relationship Modeling
0.7520.947R2
-2.07-. 353C=C
-.845-.211CH
7.08E-2.795CH3
-.320.269CH2
-1.544-1.451C
0.890.10PRESS/SSY
.584.453H (on C=C)
.296.810BR
.569.612CL
.382.734AC
Log Km Log VmaxcStructural feature
Application (chloroethane)
C C
H
H
H
H
H
CL
Log Vmaxc = 0.795 + 0.269 + 0.612 = 1.676 vs 1.79
101.68 * BW0.7 Human (BW=70 kg) = 937 µmol/hr
Rat (BW=0.25 kg) = 18.1 µmol/hr
Log Km = 0.071- 0.32 + 0.569 = 0.26 vs 0.19 µM
Interspecies extrapolation of metabolism constants Turnover rate for one species CYP concentration + tissue volume Interspecies extrapolation of Vmax… Current approach:
Classification of substrates (molecular volume, log P)
Isozyme-specific substrates ( in vitro QSARs) Species extrapolation based on protein [C]
and tissue volume
Extrapolation
INVARIANT:Species SPECIFIC:
Vmaxc
Km
Blood:air PC
Flows
Volumes
Enzyme [C]
Interspecies extrapolation of PK of organic chemicals
Species SPECIFIC:
Fluid PCs
Flows
Volumes
Enzyme [C]
In h ale d c h e mic a lE xh ale d c h e mic a l
Ve
nous
Blo
od A
rterial Bloo
d
R e s t o f B od y
K id ne y s
Bra in
Liv e r
G ills
QSAR-PBPK Modeling
Parameters
Equations
Tissu adipeux
Foie
Tissu pauvrement perfusé
Tissu richement perfusé
Poumons ou branchies
Sang artériel
San
g ve
ineu
x
Ca, Qc Cv, Qc
Cex, Qv Cin, Qv
Km, Vmax Métabolisme
CvL QL
QS
QR
QF
CvS
CvR
CvF
Simulations
Physiology
Temps
Co
ncen
trati
on
Rat
QSPR-PBPK Modeling: Interspecies extrapolation of tissue concentrations
0
5
10
15
20
25
30
35
0 5 10 15 20 25
Time (hr)
Tis
su
e co
nc
entr
atio
n (
mg
/L) Catfish
FHM
Trout
Rat
Human
DOSE EFFECT
QSAR
QSARs – An alternative paradigm
Tissue doseor Blood
Conc.QSAR QSAR
PK PD
• Relative contribution of the TK and TD processes• Extrapolations based on TK determinants
Conclusions
Interspecies differences in metabolic clearance and volume of distribution can be examined using mechanism-based QSARs
PBPK modeling uniquely allows the integration of such QSARs to simulate interspecies differences in PK profiles
QSAR-PBPK models facilitate internal dose based risk assessment in multiple species(lethal and non-lethal effects)
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