Transcript QSARs for human physiological models

Species extrapolation
with PBPK models
Kannan Krishnan
Université de Montréal, Canada
Outline
 Introduction
 Rat-Human extrapolation



Single chemicals
Mixtures
QSARs
 Rat-Fish extrapolation


PBPK modeling
QSARs
 Conclusions
PBPK Models and
Interspecies Extrapolation
Inhaled Exhaled
Lungs
C
Liver
Adipose tissue
PBPK
Program
Richly perfused
tissues
Poorly perfused
tissues
STRUCTURE
T
C
RAT
or
HUMAN
T
INPUT
PARAMETERS
SIMULATIONS
Functional Representation
Amount
dAt
 Input  Output
dt
Blood flow to tissue, volume, partition coefficient
Functional Representation
Metabolic Clearance
Vmax  C
Km  C
Vmax = maximum velocity of metabolism
Km = Michaelis-Menten constant
C = concentration of chemical
Metabolizing enzyme, its levels, tissue volume
Interspecies extrapolation of PK of chemicals
Extrapolation
Species
SPECIFIC:
INVARIANT:
Species
SPECIFIC:
Blood:air PC
Vmaxc
Blood:air PC
Flows
Km
Flows
Volumes
Tissue:air
PC
Volumes
[P-450]
[P-450]
Mixture PBPK Models and Interspecies
Extrapolation
ABCDE
ABCDE
Lungs
C
Poorly
perfused
tissues
Richly
perfused
tissues
Liver
Arterial blood
Venous blood
Fat
Computer
Program
T
C
RAT
or
HUMAN
T
metabolis
m
STRUCTURE
SIMULATIONS
INPUT
PARAMETERS
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
Exposure Condition
Structure Input
@Chemical
Yellow Indicates User Input
QSAR/PBPK model – Ethyl benzene
QSAR/PBPK model:Dichloromethane
Conceptual Representation
Inspired chemical
Expired chemical
Liver
Muscle
Kidneys
Rest of Body
Arterial Blood
Venous Blood
Gills
Lungs
Cin
Pulmonary ventilation (Qv)
Cv
Gills
Cv
Ca
Cardiac output (Qc)
Ventilation limited exchange : Pb = Cv/Cex
Blood flow limited exchange :
Cex
Cex
Pb = Ca/Cin
Effective respiratory volume (Qv)
Cardiac ouput (Qc)
Cin
Ca
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
Pt:e  Po :e Fnt  0.3 Fpt   Fwt  0.7 Fpt 
Po:e
Pt:e
Fnt
Fpt
Fwt
= n-octanol:env partition coefficient
= tissue:env partition coefficient
= volume fraction of neutral lipids in tissue
= volume fraction of phospholipids in tissue
= volume fraction of water in tissue
Interspecies differences in
mechanistic determinants (PCs)
Tissue and
species
Neutral
lipid eqvt
Water eqvt
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
Muscle
Interspecies extrapolation of tissue:air partition
coefficients (Humans)
Log liver:air mecaniste
Log fat:air mecaniste
3
4.5
4
2.5
3.5
2
Log PRED
2.5
2
1.5
R2 = 0.993
Y = 0.992X
1
0.5
1.5
1
-0.5
-0.5
y = 0.9721x
R2 = 0.969
R2 = 0.8686
Y = 0.973X
0.5
0
0
0.5
1.5
2.5
3.5
-0.5
-0.5
4.5
0
0.5
Log muscle:air mecaniste
2.5
2
1.5
1
R2 = 0.933
y = 0.8858x
R2 = 0.814
Y = 0.886X
0.5
0
-0.5
-0.5
1
1.5
Log EXPTL
Log EXPTL
Log PRED
Log PRED
3
0
0.5
1
Log EXPTL
1.5
2
2.5
2
2.5
3
Interspecies extrapolation of tissue:air partition
coefficients (Fish)
Fathead minnow
100000
10000
10000
1000
y = 1.4883x
R2 = 0.9977
100
Pred PC
100000
1000
y = 2.5499x
R2 = 0.9992
100
10
10
1
1
1
10
100
1000
10000
1
10
100
Exptl PC
Exptl PC
Rainbow trout
100000
10000
Pred PC
Pred PC
Channel catfish
1000
100
y = 1.343x
R2 = 0.9981
10
1
1
10
100
Exptl PC
1000
10000
1000
10000
Application (chloroethane)
H
H
H
C
C
H
H
CL
Log Poa = 0.373+0.433 +0.785 = 1.6
Log Pwa = -0.031 -0.225 +0.471 = 0.215
Rat Pla
0.0425 *101.6 +
0.7176 *100.215 = 2.87
Trout Pla
0.0261 *101.6 +
0.7649 *100.215 = 2.29
Magnitude of Interspecies Differences
in Tissue:Water PCs
Pt :w A/B 
Po :w
Pt :a
Fnt
Fpt
Fwt
A&B
Po :w (AFnt  0.3 AFpt )  (AFwt  0.7 AFpt )
Po :w (BFnt  0.3 BFpt )  (BFwt  0.7 BFpt )
= n-octanol:water partition coefficient
= tissue:water partition coefficient
= volume fraction of neutral lipids in tissue
= volume fraction of phospholipids in tissue
= volume fraction of water in tissue
= two differents species
Interspecies Pb:w ratio
Calculated magnitude of interspecies differences in
blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
2,5
2,0
trout/catfish
trout/medaka
trout/FHM
medaka/catfish
FHM/catfish
FHM/medaka
1,5
1,0
0,5
0,0
0,001
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pb:w ratio
Calculated magnitude of interspecies differences in
blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
2,5
2,0
1,5
trout/catfish
trout/medaka
trout/FHM
medaka/catfish
FHM/catfish
FHM/medaka
1,0
0,5
0,0
0,001
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pb:w ratio
Calculated magnitude of interspecies differences in
blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
2,5
2,0
1,5
trout/catfish
trout/medaka
trout/FHM
medaka/catfish
FHM/catfish
FHM/medaka
1,0
0,5
0,0
0,001
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pb:w ratio
Calculated magnitude of interspecies differences in
blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
2,5
2,0
trout/catfish
trout/medaka
trout/FHM
medaka/catfish
FHM/catfish
FHM/medaka
1,5
1,0
0,5
0,0
0,001
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pb:w ratio
Calculated magnitude of interspecies differences in
blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
2,5
2,0
trout/catfish
trout/medaka
trout/FHM
medaka/catfish
FHM/catfish
FHM/medaka
1,5
1,0
0,5
0,0
0,001
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pb:w ratio
Calculated magnitude of interspecies differences in
blood:water (Pb:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
2,5
2,0
trout/catfish
trout/medaka
trout/FHM
medaka/catfish
FHM/catfish
FHM/medaka
1,5
1,0
0,5
0,0
0,001
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pl:w ratio
Calculated magnitude of interspecies differences in
liver:water (Pl:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
5,0
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
0,001
trout/catfish
medaka/catfish
trout/medaka
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pl:w ratio
Calculated magnitude of interspecies differences in
liver:water (Pl:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
5,0
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
0,001
trout/catfish
medaka/catfish
trout/medaka
0,01
0,1
1
10
Po:w
100
1000
10000
Interspecies Pl:w ratio
Calculated magnitude of interspecies differences in
liver:water (Pl:w) partition coefficient as a function of
n-octanol:water partition coefficient (Po:w)
5,0
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
0,001
trout/catfish
medaka/catfish
trout/medaka
0,01
0,1
1
10
Po:w
100
1000
10000
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
Structural feature
Log Vmaxc
Log Km
AC
.734
.382
CL
.612
.569
BR
.810
.296
H (on C=C)
.453
.584
CH3
.795
7.08E-2
CH2
.269
-.320
CH
-.211
-.845
C
-1.451
-1.544
C=C
-. 353
-2.07
R2
0.947
0.752
PRESS/SSY
0.10
0.89
Application (chloroethane)
H
H
H
C
C
H
H
CL
Log Km = 0.071 - 0.32 + 0.569 = 0.26 vs 0.19 µM
Log Vmaxc = 0.795 + 0.269 + 0.612 = 1.676 vs 1.79
Human (BW=70 kg) = 937 µmol/hr
101.68 * BW0.7
Rat (BW=0.25 kg) = 18.1 µmol/hr
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
Interspecies extrapolation of PK of
organic chemicals
Extrapolation
Species
SPECIFIC:
INVARIANT:
Species
SPECIFIC:
Fluid PCs
Vmaxc
Blood:air PC
Flows
Km
Flows
Volumes
Volumes
Enzyme [C]
Enzyme [C]
QSAR-PBPK Modeling
Physiology
Parameters
CvR
Poumons ou branchies
QF
Tissu adipeux
Tissu richement perfusé
CvS
Tissu pauvrement perfusé
CvL
Foie
Km, Vmax
Ca, Qc
QR
QS
Sang artériel
Sang veineux
CvF
Cex, Qv
Equations
QL
Métabolisme
Simulations
Concentration
Cin, Qv
Cv, Qc
Rat
Temps
QSPR-PBPK Modeling: Interspecies
extrapolation of tissue concentrations
35
Tissue concentration (mg/L)
30
Catfish
FHM
Trout
Rat
Human
25
20
15
10
5
0
0
5
10
15
Time (hr)
20
25
QSARs – An alternative paradigm
PK
DOSE
QSAR
Tissue dose
or Blood
Conc.
PD
QSAR
EFFECT
QSAR
• 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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