Plumbing 101
or
How a good boy went bad
Mel AndersenMcKim Conference
QSAR and Aquatic Toxicology & Risk AssessmentJune 27-29, 2006
You and me, fish, and rats are:• Collections of organs organized in parallel or series
with a continuous blood flow
• There are differences in the function of organs, their arrangement with respect to the circulation and each other, and biological content.
• Differences correlate with the evolutionary pressures and environments in which the organisms first developed and now live.
PhD - 1971
An Almost Post-Doc – 1972-1974
After such a promising start:
Joined the mammalian toxicology world with an interest in pharmacokinetics and pharmacodynamics of toxic compounds in rats and mice and extrapolation from rodents to human populations.
The Plumbing and Delivery System(Tissue Dose, not simply Applied
Dose)
Qc
Cvl
Cvf
Cvr
Cvs
Qc
Ca
QL
Qf
Qr
Qs
Ci Cx
Qp
Lung
Liver
Fat
Rapidly perfused (brain, kidney, etc.)
Slowly perfused (muscle, bone, etc.)
Describing the Individual Pieces Quantitatively
Dead Space
Lung Ventilation
Capillary Blood
InspiredAir
ExpiredAir
From: Hagaard (1924)
Body Tissue
Pulmonary Blood
Countercurrent Exchange
Problem: Estimate amount taken up in first few breaths.
QpCinhQpCexh
Cexh
QcCart
Cart
QcCven
Qc = cardiac output
Qp = alveolar ventilation
Cinh = inhaled concentration
Cexh = exhaled concentration
Cart = arterial concentration
Cven = venous concentration
Pb = blood/air partition coeffecient
Terms:
Uptake = Qc Cart = Pb Qc Qp Cinh /(Pb Qc + Qp)
Linking the Units in Parallel
Lung
Fat
Body
Muscle
Kety (1951)
Describing a Single Tissue
(venous equilibration assumption)
Qt = tissue blood flow
Cvt = venous blood concentrationPt = tissue blood partition coefficientVt = volume of tissue
At = amount of chemical in tissue
QtCart QtCvt
Vt; At; Pt
Tissue
Cvt = Ct/Pt
Terms
mass-balance equation: dAt = Vt dCt = QtCart - QtCvt
dt dt
Blood Flow Characteristics in Animals & Digital Computation
LUNG
Liver
Right heart
Kidney
Trunk
Lowerextremity
Largeintestine
Spleen
Upper body
Small intestine
Left heart
Bischoff and Brown (1961)
An application in toxicology....
Ramsey and Andersen (1984)
Alveolar Space
Lung Blood
Fat Tissue Group
Muscle TissueGroup
Richly PerfusedTissue Group
LiverMetabolizingTissue Group( )
MetabolitesVmax
Km
Cart
Ql
Cart
Qr
Cart
Qm
Cart
Qt
Cart
Qc
Calv (Cart/Pb)
QalvQalv
Cinh
Qc
Cven
Cvt
Cvm
Cvr
Cvl
2520151050
100
10
1
0.1
0.01
0.001
TIME - hours
Ven
ou
s C
on
cen
trati
on
– m
g/l
ier
blo
od
Conc = 80 ppm
Conc = 1200 ppmConc = 600 ppm
Extrapolations – Across Doses
Alveolar Space
Lung Blood
Fat Tissue Group
Muscle TissueGroup
Richly PerfusedTissue Group
LiverMetabolizingTissue Group( )
MetabolitesVmax
Km
Cart
Ql
Cart
Qr
Cart
Qm
Cart
Qt
Cart
Qc
Calv (Cart/Pb)
QalvQalv
Cinh
Qc
Cven
Cvt
Cvm
Cvr
Cvl
What do we need to add/change in the models to incorporate another dose
route – iv or oral?
IV
Oral
Styrene - Dose Route Extrapolation
100
10
1.0
0.1
0.010 0.6 1.2 1.8 2.4 3.0 3.6
Hours
IV
Sty
ren
e C
on
cen
trati
on
(m
g/l
) 10
1.0
0.1
0.010 0.4 0.8 1.2 1.6 2.0 2.4
Hours
Oral
Sty
ren
e C
on
cen
trati
on
(m
g/l
)
2.8
Alveolar Space
Lung Blood
Fat Tissue Group
Muscle TissueGroup
Richly PerfusedTissue Group
LiverMetabolizingTissue Group( )
MetabolitesVmax
Km
Cart
Ql
Cart
Qr
Cart
Qm
Cart
Qt
Cart
Qc
Calv (Cart/Pb)
QalvQalv
Cinh
Qc
Cven
Cvt
Cvm
Cvr
Cvl
What do we need to add/change in the models to describe another animal
species?
SizesFlowsMetabolic Constants
Styrene - Interspecies Extrapolation
Rat - Human
51
376
216
0.1
0.01
0.001
0.00010 1.5 3.0 4.5 6.0 7.5 9.0
Hours
Sty
ren
e C
on
cen
trati
on
(m
g/l
)
Blood
80 ppm
Exhaled Air
0 8 16 24 32 40 48
0.00001
0.0001
0.001
0.01
0.1
1.0
10
Hours
Sty
ren
e C
on
cen
trati
on
(m
g/l
)
Getting Constants for Modeling Metabolism and Closed Chamber
StainlessSteel
BellowsPump
~ 2.0L/min
CO2
Scrubber
ParticulateFilter
O2 Monitor
PressureGauge
InjectionPort
Ice Filled Pan forH2O Condensation
Desiccator JarChamber
~ 100 mL/min
INTEGRATOR
Gas Chromatograph
5 mL GasSampling Loop
Time (hours)
PP
M
CH2FCl
Time (hours)
PP
M
CH2Cl2
Dihalomethane:Closed Chamber Gas Uptake Studies
Rapid estimation of Vmax, Km for a data base to support SAR/QSAR
Then along came Jim:
Jim shows up in Dayton:
Physiologically Based Pharmacokinetic (PBPK) Modeling
Define Realistic Model
Collect NeededData
Refine Model Structure
Make Predictions
Metabolic Constants
Tissue Solubility
Tissue Volumes
Blood and Air Flows
Experimental System
Model Equations
X
X
X
X
X
XX X
Tis
sue C
on
centr
ati
on
Time
Liver
Fat
Body
Lung/Gill
Air/Water
• Establish role of partition coefficients and provide emphasis on establishing appropriate metabolic parameters in vitro
• Generate data bases suitable for SAR and QSAR modeling of PCs, Vmax, Km
• Organizing physiological and anatomical information to support modeling needs and show value of approach broadly across animal species – mammals, fish, birds, etc.- for estimating tissue dose (as concentration of parent, metabolites, area under curves, etc.)
PBPK Modeling – Getting the right data
Thank you
• Some collaborators
Jim McKim John Nichols Mike Gargas Harvey Clewell John Ramsey
Compartments in Physiological Model
for Methotrexate
T T T
Plasma
Liver G.I. Tract
r1 r2 r3
Kidney
Muscle
QK
QL - QG
QG
QM
Gut Lumen
Gutabsorption
C1 C2 C3 C4 Feces
Bischoff et al. (1971)
Compartmental PK Modeling
Collect
Data
Select
ModelFit Model to
Data
Ct = A e –kaxt + B e-kbxt
X
X
X
X
X
XX X
Tis
su
e C
on
cen
trati
on
time
k12k21
koutKOA1
A2
X
X
Tis
su
e C
on
cen
trati
on
time
XX X
X
XX