oEPA
United States
Environmental Protection
Agency
Office of Research and
Development
Washington DC 20460
EPA/600/6-88/004
February 1988
Reference Physiological
Parameters in
Pharmacokinetic Modeling
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EPA/600/6-88/004
February 1988
Reference Physiological Parameters in Pharmacokinetic Modeling
Angela D. Arms and Curtis C. Travis
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37831-6109
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, B.C. 20460
Printed on Recycled Paper
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or recommendation
for use.
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CONTENTS
Tables
Figures
Abstract
Authors, Contributors, and Reviewers iz
1. SUMMARY 1-1
2. INTRODUCTION 2-1
3. PHARMACOKINETIC MODELING 3-1
3.1. DESCRIPTION 3-1
4. PHYSIOLOGICAL PARAMETERS 4-1
4.1. BODY WEIGHTS 4-2
4.1.1. Reference Values 4-2
4.1.2. Documentation 4-2
4.2. TISSUE VOLUMES 4-4
4.2.1. Reference Values 4-4
4.2.2. Documentation 4-5
4.2.3. Values Used in Pharaaco kino tic Models 4-9
4.3. CARDIAC OUTPUT 4-17
4.3.1. Reference Values 4-18
4.3.2. Documentation 4-18
4.3.3. Values Used in Pharaacokinetic Models 4-29
4.4. CARDIAC OUTPUT DISTRIBUTION 4-30
4.4.1. Reference Values 4-30
4.4.2. Documentation 4-30
4.4.3. Values Used in Pharmacokinetic Models 4-33
iii
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CONTENTS (continued)
Page
4.5. RESPIRATION PARAMETERS 4-41
4.5.1. Reference Values 4-42
4.5.2. Documentation 4-43
4.5.3. Values Used in Pharmacokine tic Models 4-61
5. SCALING 5-1
5.1. CARDIAC OUTPUT 5-2
5.1.1. Mice 5-3
5.1.2. Rats 5-4
5.1.3. Humans 5-6
5.2. MINUTE VENTILATION 5-7
5.2.1. Mice 5-7
5.2.2. Rats 5-9
5.2.3. Humans 5-13
6. APPENDIX A: TABLE OF PARTITION COEFFICIENTS 6-1
7. REFERENCES 7-1
iv
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TABLES
Page
1-1 Reference physiological parameters 1~1
3-1 Abbreviations and symbols used in describing
a pharma co kinetic model . 3-4
4-1 Physiological parameters used for modeling 4-1
4-2 Reference body weights of mice, rats, and humans 4-2
4-3 Reference tissue volumes of mice, rats, and humans .... 4-4
4-4 Reference cardiac output of mice, rats, and
humans 4-18
4-5 Absolute cardiac output of mice 4-19
4-6 Relative cardiac output of mice 4-20
4-7 Absolute cardiac output of unanesthetized rats 4-21
4-8 Absolute cardiac output of anesthetized rats 4-22
4-9 Relative cardiac output of unanesthetized rats 4-25
4-10 Relative cardiac output of anesthetized rats 4-26
4-11 Absolute cardiac output of humans 4-27
4-12 Cardiac output values used in ph arm a co kinetic models ". . . 4-29
4-13 Reference tissue perfusion rates of mice, rats,
and humans 4-30
4-14 Reference respiration parameters of mice, rats,
and humans «, 4-43
4-15 Absolute minute volumes of unanesthetized mice 4-44
4-16 Absolute minute volumes of anesthetized mice 4-45
4-17 Relative minute volumes of unane sthetized mice 4-46
4-18 Relative minute volumes of anesthetized mice 4-46
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TABLES (continued)
4-19
4-20
4-21
4-22
4-23
4-24
4-25
4-26
4-27
4-28
4-29
4-30
4-31
5-1
5-2
5-3
5-4
5-5
5-6
5-7
5-8
5-9
5-10
5-11
Respiratory frequencies of unane sthetized mice. . .
Respiratory frequencies of anesthetized mice
Absolute minute volumes of unane sthetized rats
Absolute minute volumes of anesthetized rats
Relative minute volumes of unane sthetized rats
Respiratory frequencies of anesthetized rats
if
Alveolar ventilation used in pharmaco kinetic models ....
Constants for calculating cardiac output
Scaling cardiac output of anesthetized rats
Constants for calculating minute volume
Sealing minute volume of unane sthetized mice
Scaling minute volume of anesthetized mice
Scaling minute volume of unane sthetized rats
Scaling minute volume of anesthetized rats
Scaling minute volumes of humans ...... «
Page
4-47
4-48
4-49
4-50
4-51
4-52
4-55
4-56
4-57
4-58
4-59
4-61
4-62
5-3
5-3
5-4
5-5
5-6
5-7
5-8
5-8
5-10
5-12
5-13
vi
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FIGURES
Page
3-1 Diagram of a typical pharmaco kinetic model used to simulate
the behavior of inhaled volatile organics 3-3
vii
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AB SIS ACT
This document presents a compilation of measured value s for
physiological parameters used in pharmacokinetic modeling. The
physiological parameters include body weight, tissue volumes, cardiac
output, cardiac output distribution, and the respiration parameters.
Reference values for use in risk assessment are given for each of the
physiological parameters based on analyses of valid measurements obtained
from the literature and other reliable sources. The proposed reference
values are for generic mice and rats without regard to sex or strain.
Reference values for humans are without regard to age or sex. Differences
between the sexes in mice, rats, and humans are accounted for by scaling
the reference parameters within species on the basis of body weight.
Reference physiological parameters are for a 0.025 kg mouse, 0.25 kg rat,
and a 70 kg man.
viii
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
AUTHORS
Angela D. Arms
Office of Risk Analysis
Health and Safety Division
Oak Ridge National Laboratory
Oak Ridge, TN 37831-6109
Curtis C. Travis
Office of Risk Analysis
Health and Safety Division
Oak Ridge National Laboratory
Oak Ridge, TN 37831-6109
CONTRIBUTORS
Janis G. Pruett APPENDIX A
Information, Research, and
Analysis Department
Biology Division
Oak Ridge National Laboratory
Oak Ridge, TN 37831
REVIEWERS
The following individuals provided
peer review of this document and/or
earlier drafts of this document.
Jerry N. Blancato
Office of Research and Development
U. S. Environmental Protection Agency
Washington, D. C. 20460
Chao W. Chen
Office of Research and Development
U. S. Environmental Protection Agency
Washington, D. C. 20460
iz
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Vera Fiserova-Bergerova Thomas
Department of Anesthesiology
University of Miami School of Medicine
Miami, FL 33101
Joe L. Mauderly
Inhalation Toxicology Research Institute
Lovelace Biomedical and Environmental
Research Institute, Inc.
Albuquerque, NM 87185
Fred J. Miller
Health Effects Research Laboratory
U. S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ellen J. O'Flaherty
Institute of Environmental Health
lettering Laboratory
University of Cincinnati Medical Center
Cincinnati, OH 45267-0056
Richard W. Walentovicz
Office of Research and Development
U. S. Environmental Protection Agency
Washington, D. C. 20460
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1. SUMMARY
Table 1-1 summarizes the recommended reference physiological parameters for
use in pharmacokinetic modeling.
0.055
0.10
0.05
0.70
0.04
0.07
0.05
0.75
0.026
0.19
0.05
0.62
TABLE 1-1. REFERENCE PHYSIOLOGICAL PARAMETERS
Mouse Rat Human
Body weights (kg) 0.025 0.25 70.0
Tissue volumes
(fractions)
Liver
Fat
vac
m
Cardiac output 0.017 0.083 6.2
(1/min)
Tissue perfusion
(fractions)
Liver
Fat
VfiG
m
Minute volume 0.037 0.174 7.5
(1/min)
Alveolar ventilation 0.025 0.117 5.0
(1/min)
0.25
0.09
0.51
0.15
0.25
0.09
0.51
0.15
0.26
0.05
0.44
0.25
1-1
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2. INTRODUCTION
Pharmaco kine tics is the science of quantitatively predicting the fate
of an exogenous substance in an organism. Utilizing computational
techniques, pharmacokinetics provides the means of studying the uptake,
distribution, metabolism, and excretion of chemicals by the body. This is
accomplished by dividing the body into various anatomical compartments.
The mathematical representation of these compartments provides a
description of the time course of drug disposition throughout the body.
Pharmacokine tics eliminates some of the ambiguities in determining the risk
of human exposure to environmental chemicals and provides a basis for
evaluating the scientific assumptions upon which the risk assessment
process is based.
A recent development in the area of pharmacokine tics is the advent of
physiologically-based pharmaco kine tic (PBPK) models. Relying on actual
physiological parameters such as body weight, breathing rates, cardiac
output, blood flow rates, tissue volumes, etc., to describe the metabolic
process, the PBPK models can relate exposure concentrations to organ
concentrations over a range of exposure conditions. This report provides a
literature review of the physiological parameters used in PBPK models, and
recommends reference physiological parameters for use in risk assessment.
2-1
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3. PHARMACOKINETIC MODELING
3.1. DESCRIPTION
A pharmaco kinetic model is a set of equations that can be used to
describe the time course of a parent chemical or metabolite in an animal
system. There are two types of pharmacokinetic models: data-based and
physiologically-based (NEC, 1986). A data-based mode 1 divides the animal
system into a series of compartments which, in general, do not represent
real, identifiable anatomic regions of the body. In applying these models,
time-course concentration curves are first determined from in vivo animal
experiments. Then, model compartment volumes and rate constants are
determined by trial and error so that the model predictions lit the
empirical data. These models are useful for interpolation and limited
extrapolation within the same species. However, since the parameters in
these data-based model s generally do not correspond to physiologically-
identifiable entities, they do not allow for extrapolation across animal
species.
A physiologically-based pharmaco kinetic model is comprised of a series
of compartments representing organs or tissue groups with realistic weights
and blood flows. These models require a variety of physiological
information: tissue volumes, blood flow rates to tissues, cardiac output,
alveolar ventilation rates (for volatile compounds) and, possibly, membrane
permeabilities. The models also utilize biochemical information such as
air/blood partition coefficients, and metabolic parameters. The uniqueness
of the physiologically-based approach is this reliance on measured
physiological and biochemical parameters. An appealing aspect of these
physiological models is that they allow ready extrapolation of observed
3-1
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experimental results from a test species to an untested species simply by
placing the appropriate physiological and biochemical parameters in the
model. Similarly, the effect of route of administration can be
investigated by allowing for different administration pathways.
It should be pointed out that no one pharmacokine tic model can be used
to determine the distribution of all chemicals. The number of compartments
and the way they are connected will vary from chemical to chemical
depending upon the chemical's metabolic behavior and the nature of the
questions being asked concerning dose to target tissues.
Despite this fact, most physiologically-based pharmacokine tic models
in current use divide the body into four physiological groups, all
connected by the arterial and venous blood flow pathways (see Figure 3-1
and Table 3-1). The first group is the vessel-rich group (VUG) and is made
up of those tissues most profusely supplied with bloodvessels. These
include the brain, heart, kidney, and viscera. The second group is
composed of muscle and skin and is called the muscle group, (MB). The
third group is composed of adipose (fat) tissue. The fourth group contains
organs with a high capacity to metabolize (principally liver). , Each tissue
group is described mathematically by a set of differential equations which
calculate the rate of change of the amount of chemical in each compartment.
Metabolism, occurring chiefly in the liver, is described by a combination
of a linear metabolic component and a Michael is-Menten component accounting
for saturable metabolism. Again, we stress that other model descriptions
are possible, but they will, in general, have the same physiological
parameters.
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ORNL-OWG H42MR
o.,.
^inh
°> t
c... "-
C.f
C,m
C,,
c,,
ALVEOLAR
SPACE
LUNG
BLOOD
FAT
TlCCl 1C
GROUP
MUSCLE
GROUP
VESSEL
Q1/*U
GROUP
LIVER
METABOLIZING
TISSUE
GROUP
Q.,v
c... *
Qb
c.,,
Of
C.r,
t Qm
1 c.rl
Or
' c.rl
Q,
" c.rl
METABOLITES
(LINEAR PATHWAY)
METABOLITES
(MICHAELIS-MENTEN)
FIGURE 3-1.
Ditfraa of i typical pbmacokinetic
odel used to «i«ultte the behavior
of inhaled volatile organic*. The
odel divides the body into four
physiological groups, all connected
by blood flow pathways. The symbols
are defined in Table 3-1.
3-3
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TABLE 3-1. NOMENCLATURE USED IN DESCRIBING A
PHYSIOLOGICALLY-BASED PHARMAOOKINETIC MODEL
Alveolar ventilation rate (liters air/or)
Concentration in inhaled air (mg/liter air)
Calv Concentration in alveolar air (mg/liter air)
Xb Blood/air partition coefficient (liters air/liters blood)
Qb Cardiac output (liters blood/hr)
Cart Concentration in arterial blood (mg/liter blood)
Cyen Concentration in mixed venous blood (mg/liter blood)
Vmax Michaelis-Menten metabolism rate (mg/hr)
Km Michael is constant (mg/liter blood)
Kf Linear metabolism rate (hr~l)
Am Amount metabolized in the liver (mg)
Qi Blood flow rate to tissue group i (liters blood/hr)*
Vi Volume of tissue group i (liters)
Ci Concentration in tissue group i (mg/liter)
Ai Amount in tissue group i (mg)
Cvi Concentration in venous blood leaving tissue group i (mg/liter blood)
Xi Tissue/blood partition coefficient for tissue i (liters blood/liter i)
Xi/a Tissue/air partition coefficient for tissue i (liters air/liter i)
k Gavage or oral rate constant (hr~l)
DO Total quantity of PCE absorbed via gavage route (mg)
"Subscripts (i) for tissue groups or compartments:
1 Liver (metabolizing tissue group)
f Fat tissue group
r Vessel-rich tissue group
m Muscle tissue group
3-4
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4. PHYSIOLOGICAL PARAMETERS
The physiological parameters typically used in pharmacokine tic
modeling are listed below.
TABLE 4-1. PHYSIOLOGICAL PARAMETERS
USED FOR MD EEL ING.
PARAMETERS
Body weight (kg)
Cardiac output (1/min)
Minute volume (1/min)
Alveolar ventilation (1/min)
Physiological dead space (%)
'Frequency (breaths/min)
ORGANS
(Volumes and Blood Flows)
Liver
Fat
Vessel-Rich Group
Muscle Group
Measured values of these parameters in mice and rats are age, sex, and
strain-dependent. For example, female rats tend to have higher mass-
specific ventilation rates than males, and young rats have values higher
than mature rats. In addition, the status of the animals during
measurement (body position, conditioning, etc.,) and the measurement
technique can have substantial influences. Lack of data for many
physiological parameters, however, limits attempts to account for these
factors. Our reference parameters are for a generic mouse or rat, without
regard to sex or strain. Differences between sexes are accounted for by
4-1
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scaling the reference parameters within species on the basis of body
weight. Reference physiological values for humans are for a resting 70 kg
man. For rodents, the reference physiological parameters are for a 0.025
kg mouse and a 0.25 kg rat at rest.
We will now review the measured values of these parameters found in
the literature. Each section is organized as follows: first, a summary
table of the recommended reference values is presented; then a literature
review is undertaken to support the recommended reference values; and
finally, a summary of the actual values of parameters used in various
ph arm a co kinetic models is presented.
4.1. BOD7 WEIGHTS
4.1.1. Reference Values
TABLE 4-2. REFERENCE BODY WEIGHTS
Mice Rats Human
0.025 kg 0.25 kg 70.0 kg
4.1.2. Documentation of Reference Values
Mice
The U.S. Environmental Protection Agency (1980) recommends a standard
body weight of 0.03 kg for an adult mouse. Other reported standards in the
literature include 0.035 kg (ARS/Spr ague-Daw ley, 1974), 0.023 kg
(Bozenbanm, 1982) and 0.02 kg (Lehman, 1959). Altnan and Dittmer (1972)
4-2
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provided growth data on seven strains of mice from birth to about six
months of age, by which time their body weights were considered stable.
The mean terminal body weight for both sexes of all strains combined was
0.032 kg (Durkin, 1985). Therefore, the reference value of 0.03 kg
recommended by the EPA seems reasonable. However, most pharmacokine tic
studies are performed on mice before they reach terminal body weight. For
the purposes of pharmacokine tic modeling, we are recommending a reference
body weight of 0.025 kg.
Rats
The U.S. EPA (1980) recommends a standard body weight of 0.35 kg for
an adult rat. Other reported standards in the literature were 0.45 kg
(ARS/Spr ague -Daw ley, 1974), 0.25 kg (Boxenbaum, 1982) and 0.40 kg (Lehman,
1959). Growth data for two strains of rats were provided by Altaian and
Dittmer (1972), in which the mean terminal body weight for both sexes and
strains combined was 0.334 kg (Durkin, 1985). Thus, the reference value of
0.35 kg for rats proposed by the EPA seems justifiable; however, most
pharmacokine tic studies are performed on rats before they reach terminal
body weight. For the purposes of pharmacokine tic modeling, we are
recommending a reference body weight of 0.25 kg.
Humans
The International Commission on Radiological Protection (ICRP)
recommends a body weight of 70 kg for an adult reference man (Snyder et
al., 1975). This value is derived from the total body weight of organs,
tissues, and components assumed to include blood vessels and other body
fluids. The U.S. EPA (1980) concurs with the ICRP (1975) in recommending
4-3
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70 kg as the acceptable reference value for an adult man.
4 .2 . TISSUE VCLUJES
Tissue volumes cited in pharmacokine tic models generally reference the
power functions reported by Adolph (1949). When these functions are
applied to mice and rats, they are only approximately correct. It seems
prudent to base tissue volumes on direct measurements when possible;
however, they can be determined indirectly through optimization of the
appropriate parameters in a pharmacokine tic model.
4.2.1. Reference Values
Reference tissue volumes are presented in Table 4-3 as a percentage of
total body weight. Tissue volumes in liters may be obtained by multiplying
total body weight (section 4.1.) by the tissue volume fraction and assuming
that one kilogram of tissue has a volume of one liter.
TABLE 4-3. REFERENCE TISSUE VCLUJE FRACTIONS
Mouse Rat Human
Liver 0.055 0.04 0.026
Fat 0.10 0.07 0.19
VBG 0.05 0.05 0.05
1C 0.70 0.75 0.62
4-4
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4.2.2. Documentation of Reference Values
Data indicate that the liver grows steadily throughout life and remains in
a fairly constant relationship to body weight. Liver weight/body weight
ratios appear to be highly strain-dependent.
Liver
Liver weight/body weight ratios in mice are more variable than in
rats, ranging from 3.5 to 8.0%, depending on strain. Specter (1956)
recorded liver volume measurements of 5.63% of body weight for the jumping
mouse and 4.56% of body weight for the meadow mouse. Kurnick and Kernen
(1962) reported that after weaning (10 weeks), liver weight maintained a
uniform relationship to body weight (4.5 to 5.8%) in mice. Bischoff et al .
(1971) reported a value of 6.0%, while Tuey and Matthews (1980) found a
value of 5.8%. On the basis of limited data, Crispens (1975) reported
values of about 3.5%. Gellatly (1975) reported the liver weight of mice on
a stock pelleted diet (standard diet) as 5.64% of body weight for males and
5.44% for females.
Fieri et al. (1980) found male Balb/c mice at 2 months of age had a
liver weight/body weight ratio of 4.8%, compared to a 4.4 to 4.5% range at
12 to 24 months. Kj el lit rand et al. (1981) reported a liver weight/body
weight range of 3.6 to 5.2% in control NIRI mice weighing 0.027 to 0.036
kg. Ruebner et al. (1984) reported liver weight/body weight ratios in
three strains of control mice. In male C57B1/6 mice, 43 to 132-weeks old,
the liver weight/body weight range was 4.7 to 7.7%. The geometric mean of
the values was 5.68%. In male C3H/He mice, 41 to Ill-weeks old, the liver
4-5
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weight/body weight range was 4.3 to 8.0%. The geometric mean of the values
was 5.48%. In male B6C3Fi mice, 21 to 119-weeks old, the liver weight/body
weight range was 4.0 to 7.3%. The geometric mean of the values was 5.6%.
De Marte and Enesco (1986) reported a liver weight/body weight ratio of
5.7% for eight-week old male Swiss Albino mice weighing 0.034 kg. For mice
24 to 78-weeks old, the percentage remained fairly constant from 4.2 to
4.7%.
The above data generally indicate that young mice have liver
weight/body weight ratios higher than older mice. Based on body weight,
oar reference mouse of 0.025 kg would qualify as a young mouse. Therefore,
the reference liver volume of 5.5% of total body weight is a reasonable
one.
Jackson (1913) found that in the albino rat the liver was on the
average 4.42% of total body weight at one year of age. Webster et al.
(1947) determined liver weight/body weight ratios in 500 Albino rats with
no consideration given to age. Rats weighing 0.250 kg gave a liver
weight/body weight ratio of 4.09% and 0.300 kg rats, 4*.0%. Addis and Gray
(1950) found a range of 3.0 to 6.0% in Albino rats; the 6.0% value was for
young rats. No values higher than 3.8% were found for rats weighing more
than 0.200 kg. De Lector-Israel (1971) cited a liver weight/body weight
ratio of 3.2% for control rats 18 to 24-months old and 3.1% for control
rats 24 to 27-month s old. Coniglio et al. (1979) studied the liver
weight/body weight ratio as a function of age in male Fischer rats. They
found body weight reached its peak at 12 months, then declined steadily
from 12 to 30 months. From six to 20 months, the liver weight/body weight
ratio remained fairly constant at 3.1 to 3.5%. For a young rat 2 to 4-
months old, the liver weight/body weight ratio was 3.8%. Kj el 1st rand et
4-6
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al. (1981) reported a liver weight/body weight ratio of 3.89 to 4.29% in
control Spr ague-Daw ley rats weighing 0.200 to 0.394 kg. Van Bezooijen
(1984) reported liver weight/body weight ratio as a function of age in six
different strains of rats. From one to 27 months, the male Fischer 344 rat
gave a liver weight/body weight ratio of 2.9 to 2.7%, declining with age.
Similar findings were reported for both the male and female Wistar rat and
the male and female WAG/Rij rats. Male Spr ague-Daw ley rats also showed a
decline in the liver weight/body weight ratio with a range of 4.5 to 3.4%
from three to 16 months of age. A measured liver volume percentage of 4.0%
of body weight was reported by Lutz et al. (1977) and a range of 4.2 to
6.3% by Jansky and Hart (1968).
The above data indicate that liver weight/body weight ratios in rats
decline with age. Based on body weight, our reference rat of 0.250 kg
would qualify as a young rat. Therefore, the reference liver volume of
4.0% of total body weight is a reasonable one.
A liver volume fraction of 2.6% in the adult reference man is recorded
in ICRP (1975; Boyd, 1941). Sherlock (1968) reported the liver comprised
2.0% of the adult body weight. DeLand and North (1968) found a linear
relationship exists between liver weight and body weight. They reported a
liver weight volume of 2.2% in a 70 kg man. We are recommending a
reference human liver volume of 2.6%.
Fat VolT""e
The recommended fat volume fraction for mice is supported by measured
values of 9.8% (Tuey and Matthew*, 1980). and an average of 10.7% (range of
8.3 to 15.5%) for four different strains of mice (Dawson, 1970). Dawson
(1970) found that body weight was not a good predictor of fat content in
4-7
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the four strains of mice. We recommend a reference fat volume percentage
for mice of 10%.
An empirical determination of 7.0% of the body fat fraction of rats
was reported by Caster et al. (1956)and Lutz et al. (1977). Reed et al.
(1930), feeding rats special diets rich in fats and carbohydrates, reported
an average value of 8.8%. The fat volume percentage in humans varies from
11.5 to 36% in males and 15 to 38% in females. We follow Reference Man and
recommend a fat volume percentage of 19.0%.
VRG and BIG Volumes
The VRG and muscle volumes are not necessarily supported by eapirical
measurements since these compartments are difficult to identify. The VRG
as defined by one investigator may include or delete organs considered in
another's definition of VEG. In order to be exact, it becomes necessary to
summate measured values from the individual organs which comprise the VRG.
For example, Ramsey and Andersen (1984) include the brain, heart, kidney.
and viscera in their definition of VRG. To obtain an accurate measured
value for the VRG, one would have to sumaate the individual measurement s of
the four organs to recommend a total value for the VRG.
Our definition of 1C includes the muscle and skin. Skeletal muscle
represents 40% of total body weight. The weight of this tissue includes
the connective tissue, bloodvessels, blood, lymph, etc., which is normally
associated with skeletal muscle (ICEP, 1975). Our reference muscle volume
value of 62% also includes smooth muscle. Skin accounts for 3.7% of total
body weight in a 70 kg man.
4-8
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4.2.3. Values Used in Pharmacokinetic Models
Since direct measurement of many of the physiological parameters used
in pharmacokine tic models is difficult, many investigators believe that the
best determination of the parameters results from optimization. It is
important to clarify that the physiological parameters used in these model
simulations produce the best fit to experimental data and may not represent
physiological values for a reference man. We now review the combination of
empirically-determined and optimized parameters for tissue volumes which
have appeared in the literature. The values are given as a percentage of
total body weight for each species.
Mice
Bischoff et al. (1971) used tissue volumes verified from laboratory
measurements. The tissue volumes for a 0.022 kg mouse were obtained for
six compartments:
Tissue Percent
Blood 7.6
Muscle 45.0
Liver 5.9
Kidney 1.5
61 tract 6.8
Gut lumen 6.8
The gastrointestinal tract and the gut-lumen were the two tissue groups not
independently measured. Total tissue volume accounted for approximately
74% of body weight.
Dedrick et al. (1973) based most of his tissue volumes for a 0.022 kg
mouse on the values reported by Bischoff et al. (1971).
4-9
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Tissue Pe r co nt
Blood 7.6
Lean 45.0
Liver 5.9
Kidney 1.5
Heart 0.43
Gut lumen 6.8
Marrow 2.7
Unlike Bischoff (1971). Dedrick did not include a separate compartment for
the gastrointestinal tract. Marrow tissue represented approximately 3.0%
of body weight and heart tissue 0.43%. Total tissue volume accounted for
70% of total body weight. Neither Bischoff (1971) or Dedrick et al. (1973)
recognized fat as a tissue compartment.
Tney and Matthews (1980) provided physiological values for a 0.038 kg
mouse, using the same tissue volumes for the blood, muscle, and gut lumen
compartments as Dedrick et al. (1973). The average values for the skin and
fat compartments were 14.5 and 9.8% of body weight, respectively, based on
measurements obtained from complete dissection of mice in their laboratory.
Total tissue .volume accounted for 89% of the total body weight of the
mouse.
Ramsey and Andersen (1984) used the physiological values for a 0.022
kg mouse suggested by previous investigators with one important exception.
They included fat as a tissue with a volume representing 9.0% of body
weight.
Tissue Percent
Liver 4.0
Fat 9.0
Richly perfused 5.0
Muscle 73.0
4-10
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The SUB of the tissue volumes accounted for 91% of total body weight of the
mouse, with the remaining 9.0% designated as skeletal tissue. Unlike
previous investigators. Ramsey and Andersen (1984) did not specify a blood
volume, since the blood did not act as a significant repository for the
chemical under investigation.
Andersen et al. (1987) reported the following physiological values for
a 0.0345 kg mouse:
Ti ssue Per cent
Liver 4.0
Fat 4.0
Rapidly perfused 5.0
Slowly perfused 78.0
In summary, values used in pharmacokinetic modeling for mice tissue
volumes varied from 4.0 to 6.0% for the liver, 4.0 to 9.0% for fat, 50% for
VRG and 73 to 78% for the muscle group.
Rats
Bischoff et al. (1971) provided tissue volumes for a 0.200 kg rat
based on his previous work and the correlations of Adolph (1949):
Ti ssue Pe r ce nt
Blood 7.5
Muscle 50.0
Kidney 0.95
Liver 4.15
GI tract 5.5
Gut lumen 5.5
Tissue volumes accounted for approximately 74% of total body weight.
4-11
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Bischoff's model neglects the fat compartment.
Harrison and Gibaldi (1977) gave tissue volumes for a 0.360 kg rat
based on measurements by Thompson and Hollis (1958). Jansky and Hart (1968)
and the correlations of Adolph (1949):
Tissue Percent
4.92
Skeletal muscle 50.0
Kidneys 0.94
Liver 3.72
Heart 0.50
GI tissues 3.0
61 co nte nt s 4.8
Skin, fat. etca 25.0
a Miscellaneous compartment
for all other body regions
Harrison and Gibaldi (1977) included the heart as a separate compartment,
in addition to recognizing fat as a miscellaneous compartment for all other
body regions (skin, etc). The sum of tissue volumes accounted for
approximately 93% of total body weight.
Lutz et al. (1977) gave the following tissue volumes for a 0.250 kg
rat:
Tissue Percent
Blood 9.0
Muscle 50.0
Liver 4.0
Skin 16.0
Fat 7.0
Gut lumen 5.6
Lutz et al. (1977) based their muscle volume of 50% of total body weight on
the data of Bischoff et al. (1971). Liver volume was measured; skin and
adipose (fat) tissues represented average values obtained by laboratory
dissection of the rats. These values are also consistent with the
4-12
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previously published data of Freudenberger (1933) and Reed e t al. (1930).
Tissue volumes accounted for approximately 92% of total body weight.
Ramsey and Andersen (1984) reported tissue volumes for a 0.30 kg rat
as:
Tissue Percent
Liver 4.0
Fat 9.0
Richly perfused 5.0
Muscle 73.0
Total tissue volume accounted for 91% of total body weight.
Fi serova-Ber gerova and Hughes (1983) estimated the following tissue
volumes (liver designated as a separate compartment) for a 0.250 kg rat:
Tissue Percent
Liver 4.0
Fat 0.40
VBG 5.6
Muscle 72.0
Another compartment accounting for 15.4% of the total tissue volume
represented the skeleton, blood, and lungs. The parameters for the rat
were tested in a model simulation of halothane in a 0.200 kg rat
(Fi serova-Ber gerova and Kawiecki, 1984). The fat parameter is quite low in
comparison with other model simulations. This can be attributed to the
young age of the rat under study and the desire to obtain the best fit to
experimental data (Fi serova-Ber gerova, 1987) .
Andersen et al. (1987) reported tissue volumes for a 0.233 kg rat:
4-13
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Tissue Pe r ce at
Liver 4,0
Fat 7.0
Rapidly perfused 5.0
Slowly perfused 75.0
Humans
Mapleson (1963) used the following tissue percentages in his model
simulation:
Tissue Percent
Adrenals 0.11
Kidneys 1.52
Thyroid 0.09
Gray matter 1.60
Heart 0.64
Other small organs and glands 0.30
Liver plus portal system 6.97
White matter 1.21
Red marrow 2.10
Muscle 43.38
Skin plus nutritive shunt 4.33
Non-fat subcutaneous 6.91
Fat 14.46
Each value listed includes the volume of blood in equilibrim with the
tissue. Bone cortex, fatty marrow tissue, and arterial and venous blood
accounted for approximately 21% of total tissue volume.
Eger (1963) recommended the following tissue volume percentages for a
70 kg man:
4-14
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Ti s sue Pe r ce nt
VUG 8.6
Fat 21.0
Muscle 47.0
VPG 18.0
Eger's VBG included the brain, heart, kidneys, hepatoportal system (liver)
and the endocrine glands. The VPG included bone and cartilage.
Bischoff et al. (1971) provided the following tissue volumes for a 70
kg man:
Tissue Pe r ce nt
Blood 7.15
Muscle 50.0
Kidney 0.40
Liver 2.0
GI tract 3.0
Gut lumen 3.0
The gut and gut-lumen volumes were not independently measured, but are
actually effective values. Total percentage of tissue volumes represented
66% of body weight for a 70 kg man. Bischoff neglects the fat compartment
for man.
The tissue volumes cited by Dedrick et al. (1972) were essentially
taken from the data of Mapleson (1963):
Tissue Percent
Blood
Liver
Gut
Heart
Kidney
Lean
Marrow
3.8
2.4
4.5
0.64
1.5
38.6
2.8
4-15
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Each values listed includes the volume of blood in equilibrium with
the tissue. Calculation of the liver, and gat values were derived from
Mapleson (1963) as well as other sources. The muscle value was lowered to
38.6% from the original value of 58.7% to achieve an adequate simulation of
the data (Dedricket al., 1972).
Fiserova-Bergerova et al. (1984) estimated the following tissue
volumes for a 70 kg man at rest:
Tissue Percent
Liver 4.0
Fat 15.0
VBB 5.0
Muscle 49.0
The VEG included brain, gastrointestinal tract, glands, heart, kidneys, and
spleen. The muscle group included muscles and skin, and the fat
compartment included adipose tissue and white marrow.
Ramsey and Andersen (1984) provided the following tissue volumes for
an 83 kg man:
Tissue Percent
Liver 4.0
Fat 9.0
Richly perfused 5.0
Muscle 73.0
These tissue volumes were assumed to be proportional to body weight, and
were scaled up in direct proportion to the ratio of body weights of a man
to that of the rat (i.e., 83 kg/0.30 kg = 277. Ramsey and Andersen, 1984).
The 9% fat value for a 70 kg man is an unrealistic reference physiological
value, but represents a good fit to the experimental data. The sum of the
4-16
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tissue volumes represented 91% of tie total body weight for an 83 kg man.
Droz (1985) used the following tissue volumes for his model
simulation:
Tissue Pe r ce nt
Liver 2.4
Fat 16.0
VBG 10.0
Muscle group 52.0
These values are for a 70 kg man at rest.
Andersen et al. (1987) reported the tissue volumes for a 70 kg man.
The volume percentages are:
Tissue Percent
Liver 3.14
Fat 23.1
Rapidly perfused 3.71
Slowly perfused 62.1
These percentages are in close accord with data from the medical literature
(ICRP, 1975; Davis and Mapleson, 1981). The 23.1% tissue fraction for fat
in humans is much closer to the ICRP recommendation of 19% than the 9% used
by Ramsey and Andersen (1984).
4.3. CARDIAC OUTPUT
Cardiac output is defined as the volume of blood pumped by each
ventricle of the heart per minute. Cardiac output can be determined by
multiplying the heart rate and the volume of blood ejected by each
ventricle during each beat (Vander et al., 1975):
4-17
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Cardiac output = heart rate z stroke vclone
The major determinant of cardiac output in all species is the oxygen demand
of the tissues. During physical activity, cardiac output increases, but to
a smaller extent than alveolar ventilation (Astrand, 1983). As a result,
the perfusion-ventilation ratio is decreased by exercise. Thus, the ratio
of cardiac output to alveolar ventilation decreases from a value of 1.3 at
rest to a value of 0.4 to 0.5 with mild activity and a value of 0.4 with
strenuous activity (Astrand, 1983).
4.3.1. Reference Values
Several direct laboratory measurements of cardiac output in rats and
humans are available in the literature. However, we were only able to
locate two direct measurements of cardiac output in the mouse. Based on
data available to us we are recommending the following reference values for
cardiac output (1/min):
TABLE 4-4. REFERENCE CARDIAC OUTPUT VALUES
Mouse Rat Human
(0.025 kg) (0.25 kg) (70.0 kg)
0.017 1/min 0.083 1/min 6.2 1/min
4.3.2. Documentation of Reference Values
The reference cardiac output of 0.017 1/min for mice was calculated
using the power function suggested in section 5.1, using the reference
mouse body weight of 0.025 kg. The reference cardiac output of 0.083 1/min
4-18
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for the rat was also calculated using the power function suggested in
section 5.1, using the reference rat body weight of 0.25 kg.
Mice
TABLE 4-5. ABSOLUTE CARDIAC OUTPUT OF MICE
CO Method Ref.
(1/min)
0.0110 1 Gjedde and Gjedde (1980)
0.0118 2 Wetterlin and Pettersson (1979)
0.0160 - Blizard and Welty (1971)
1. Indicator fractionation
2. Soluble indicator
Gjedde and Gjedde (1980) measured cardiac output in anesthetized,
female BALB/c mice weighing 0.025 kg. Using the indicator f ractiona tion
technique developed by Sapirstein (1958), cardiac output was determined to
be 0.011 1/min. Relative cardiac output was 0.440 1/min-kg.
Wetterlin and Pettersson (1979) determined cardiac output in 35 male
and female Nlftl, anesthetized mice. The mice weighed between 0.025 to
0.030 kg. Cardiac output measured 0.0118 to 0.0028 1/min. Relative
cardiac output determined from this study was 0.435 1/min- kg.
Blizard and Welty (1971) measured heart rates in 70 unane sthetized,
unrestrained mice with an average body weight of 0.0225 kg. Mean heart
rate 60 minutes after handling was 537.4 min"1- Using an average stroke
volume of 0.03 ml (Wetterlin and Pettersson, 1979) for anesthetized mice,
we obtain an estimate of cardiac output in mice of 0.016 1/min, with a
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relative cardiac output of 0.711 1/min-kg.
Table 4-6 summarizes data available on the relative cardiac output of
mice.
TABLE 4-6. RELATIVE CARDIAC OUTPUT OF MICE
(1/min-kg)
£0 Range Ref.
0.440 - Gjedde and Gjedde (1980)
0.435 0.333 - 0.537 Wetterlin and Pettersson (1979)
0.711 - Blizard and Welty (1971)
Rats
Measurements of absolute cardiac output of unane sthetized rats are
listed in Table 4-7:
4-20
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TABLE 4-7. ABSOLUTE CARDIAC OUTPUT OF UNANESTHETIZED RATS
CO
(1/min)
0.0730
0.0918
0.1010
0.1107
0.1167
0.1193
0.1340
Method
1
2
2
2
2
2
3
Ref.
Guy ton (1947)
Popov ic and Kent
Jansky and Hart
Tsuchiya et al .
Tsuchiya et al.
Tsuchiya et al.
Coleman (1974)
(1964)
(1968)
(1978)
(1978)
(1978)
1. Respirograph
2. Pick
3. Dye-dilution
Guy ton (1947) used the oscilloscopic respirograph to determine cardiac
output in 35 white rats with an average weight of 0.113 kg. Cardiac output
was 0.0730 1/min.
Popov ic and Kent (1964) conducted an extensive, 120-day study of
cardiac output in unane sthetized rats. Using the Pick method, 'they
determined a cardiac output of 0.0918 1/min in rats weighing 0.319 kg.
Jansky and Hart (1968) measured cardiac output in warm- and cold-acclimated
rats and reported a cardiac output of 0.1010 1/min. Average weight of the
rats was 0.355 kg. Tsuchiya et al. (1978) measured cardiac output in three
strains of conscious rats. Six male Wistar-Kyoto rats, weighing 0.447 ±
0.020 kg, gave an average cardiac output of 0.1107 1/min. Eight male
hypertensive rats of the Akamoto-Aoki strain, weighing 0.390 + 0.012 kg,
provided an average cardiac output of 0.1167 1/min. Five male American
Wistar rats, weighing 0.473 ± 0.010 kg, recorded a mean cardiac output of
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0.1193 1/min. All experiments were done using the direct Pick principle.
Coleman (1974) measured cardiac output in conscious Wistar rats weighing
0.512 ± 0.016 kg using a modified dye-dilution technique. Cardiac output
was 0.134 1/min.
Measurements of absolute cardiac output of anesthetized rats are
listed in Table 4-8.
TABLE 4-8. ABSOLUTE CARDIAC OUTPUT OF ANESTHETIZED RATS
CO
(1/min)
0.027
0.040
0.047
0.047
0.063
0.070
0,079
0.093
0.095
0.097
0.100
0.120
Method
4
1
1 (a)
_
1. 6
5
3
3
3
3
3
2
Ref.
Walsh et al . (1976)
Walsh et al. (1976)
Blood et al. (1950)
Clarksoa (1956)
Chiu (1974)
Ac term a nn and Veress (1980)
Dytmdikova et «1 . (1981)
Dyradikova et al . (1981)
Lin et al. (1970)
Dyundikova et al . (1981)
Dyundikova et al . (1981)
Holt et al. (1968)
1. Pick (a) a trial cannula
2. Indicator-dilution
3. Theraodilution
4o Probe method
5. Microsphere
6. Catheterization
4-22
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Walsh et al. (1976) reported the cardiac output for 15 Spr ague-Daw ley
and 12 Wistar rats under basal resting conditions. Using the direct Pick
procedure for determination of cardiac output, Walsh et al. (1976) compared
the results with simultaneous electromagnetic flowmeter techniques (Probe
method). Body weight ranged from 0.175 to 0.250 kg for both the Sprague-
Dawley and Wistar rats. Pick cardiac output measurements in Spr ague-Daw ley
and Wistar rats under basal resting conditions were 0.041 1/min and 0.040
1/min, respectively. Using the Probe method, Spr ague-Daw ley rats had a
0.029 1/min reading for cardiac output, while the Wistar rats measured
0.027 1/min. Thus, cardiac output using the Pick procedure was between 40
and 50% greater than with the Probe method.
Blood et al. (1950) determined cardiac output in young adult,
anesthetized rats at normal and high altitudes. The University of Denver
strain mice weighed between 0.180 to 0.200 kg. The mean cardiac output for
52 rats at normal altitude was found to be 0.0465 ± 0.0156 1/min. Claris on
(1956) reported cardiac output in an anesthetized, 0.18 kg rat as 0.047
1/min, with a range of 0.015 to 0.079 1/min.
Chiu (1974) used a modified version of the catheterization technique
popularized by Popovic and Kent (1964) and used again by Jansky and Hart
(1968). Chiu measured cardiac output in 25 male adult albino Wistar rats,
weighing 0.304 ± 0.005 kg, under "conscious" conditions. Cardiac output
was 0.0625 ± 0.0028 1/min. This measurement was obtained when the rats
regained consciousness following administration of 40 mg/kg i.p. of sodium
pentobarbi tal. In compari son with other measurements for unane sthetized
rats, it is clear the value reported by Chiu (1974) is more in line with
those of anesthetized rats. Chiu (1974) suggested cardiac output should
not be affected by the residual effects of light anesthesia. However, the
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amount of sodium pentobarbital used for the rats is equal to the amount
reported for anesthetized rats in the study by Popovic and Kent (1964).
Chiu (1974) did not specify the time lapse between the administration of
the anesthetic and the regaining of consciousness.
Lin et al (1970) measured cardiac output in anesthetized, Sprague-
Dawley rats in an attempt to prove the reliability of the thermodilution
method for measuring cardiac output. Cardiac output ranged from 0.066 to
0.124 1/min for rats that ranged in weight from 0.330 to 0.494 kg. The
author notes that the thermodilution method results in higher cardiac
output values than those obtained by other methods.
Ackermann and Veress (1980) measured cardiac output in 24 male
Spr ague -Daw ley rats. Body weight was 0.394 + 0.008 kg. Cardiac output was
measured as 0.0701 1/min. Dyundikova et al. (1981) measured cardiac output
in male rats as a function of age. Rats weighing 0.345 kg (ages 5 to 9
months) gave a cardiac output reading of 0.100 1/min. Ten to 16-month old
rats, weighing 0.383 kg, gave a cardiac output reading of 0.097 1/min.
Seventeen to 23-month old rats, weighing 0.420 kg, gave a cardiac output
reading of 0.078 1/min. Twenty-four to 29 month old rats, weighing 0.411
kg, gave a cardiac output reading of 0.093 1/min. Thus, cardiac output
decreases with age, reaching a minimum at 17 to 23 months. However, rats
older than 24 months approached the values found for rats between 17 to 23
months (Dyundikova et al. , 1981). Holt et al. (1968) reported a cardiac
output measurement of 0.12 1/min in a controlled experiment using three
anesthetized rats weighing 0.49 kg.
Relative cardiac output measurements of unane sthetized and
anesthetized rats are summarized in Table 4-9 and Table 4-10.
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TABLE 4-9 . RELATIVE CARDIAC OUTPUT OF UNANESTHETTZED RATS
(1/min-kg)
CO Range Ref.
0.248 - Tsucniya et al. (1978)
0.252 - Tsuchiya et al. (1978)
0.265 0.252 - 0.278 Coleman (1974)
0.278 0.255 - 0.301 Malik et al. (1976)
0.285 - Jansky and Hart (1968)
0.286 0.261 - 0.311 Popovic and Kent (1964)
0.299 - Tsnchiya et al. (1978)
0.305 0.264 - 0.346 Malik et al. (1976)
0.402 0.383 - 0.421 Muller and Mannesaann (1981)
0.646 Gnyton (1947)
4-25
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TABLE 4-10. RELATIVE CARDIAC OUTPUT OF ANESTHETIZED RATS
(1/min-kg)
£0 Ranee Ref.
0.204 0.186 - 0.222 Popovic and Kent (1964)
0.205 - Sapirstein (1958)
0.207 0.203 - 0.210 Chin (1974)
0.210 0.176 - 0.242 Bollard (1959)
0.228 0.213 - 0.243 Coleman (1974)
0.238 0.196 - 0.299 Richardson et al. (1962)
0.245 - Holt et al. (1968)
0.245 0.163 - 0.327 Blood et al. (1950)
0,249 0.240 - 0.258 Richardson et al. (1962)
0.261 - Clarkson (1956)
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Humans
Measurements of absolute cardiac output of humans are summarized in
Table 4-11.
TABLE 4-11. ABSOLUTE CARDIAC OUTPUT OF HUMANS
CO
(1/min)
4.60
4.88
5.20
5.21
5.30
5.51
5.60
5.73
6.00
6.00
6.21
6.30
6.49
Method
1
6
4
2
4
5
-
6
3
5
6
-
2
Ref.
Shaw et al . (1985)
Starr and Shroeder (1940)
Frostell et al. (1983)
Astrand et al. (1964)
Reeves et al. (1961)
Cournand et al. (1945)
Guyton (1971)
Starr and Shroeder (1940)
Johnson and Miller (1968)
Stead et al. (1945)
Tanner (1949)
Cowles et al. (1971)
Brandf onbrener et al. (1955)
1. Doppler
2. Dye-dilution
3. Breath-hoi ding
4. Direct Pick
5. Catheterization
6. Ballistocardiograph
Tanner (1949) reported cardiac output data for 50 healthy men measured
by the ball istocardiograph. Mean cardiac output was 6.21 + 0.79 1/min.
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Tanner also reported cardiac output measurements by other investigators for
both males and females. Ball istocardiograph measurements ranged from 4.88
to 6.21 1/min (Starr and Shroeder, 1940; Tanner, 1949). Catheterization
resulted in cardiac output measurements of 5.51 1/min and 6.00 1/min (Stead
et al,, 1945; Cournand et al., 1945).
Guyton (1971) recommends a c&rdiac output of 5.6 liters per minute for
a normal, resting adult man.
Astrand et al. (1964) measured cardiac output in 23 healthy men and
women using the dye-dilution technique. Cardiac output at rest ranged from
3.8 to 6.7 1/min. Average cardiac output was 5.21 1/min.
Reeves et al. (1961) reported a measured value of 5.3 1/min for a
resting 72 kg man.
Johnson and Miller (1968) reported a resting cardiac output of 6.0
1/min. Shaw et al. (1985) measured cardiac output in 10 subjects using the
pulsed Doppler technique. Resting cardiac output was 4.6 ± 1.0 1/min
(range of 3.2 to 6.2 1/min). These measurements are in agreement with
those of Astrand et al. (1964).
Cowles et al. (1971) reported a cardiac output of 6.3 1/min based on a
statistical analysis of 510 measurements by 45 investigators,
Brandfonbrener et al. (1955) measured cardiac output in 67 healthy
males, 19 to 86 years of age. The mean cardiac output for a 23.6 year old
man was 6.49 1/min.
The best summaries of data for cardiac output in humans appear to be
Tanner (1949), Brandfonbrener et al. (1955). and Cowles et al. (1971).
These studies indicate that cardiac output decreases with age but is about
6.2 to 6.5 1/min for men between the ages of 20 to 30 years old. Thus, we
are recommending a reference cardiac output of 6.2 1/min.
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4.3.3. Values Used in Pharmacokinetic Models
Table 4-12 summarizes cardiac output values that have been used in
pharmacokine tic models.
TABLE 4-12. CARDIAC OUTPUT
(1/min)
Source Mouse
Mapleson (1963)
Mun son and Bowers (1967)
Dedrick and Bischoff (1968)
Bischoff et al. (1971) 0.0044
Dedrick et al . (1972)
Dedrick et al. (1973) 0.0044
Harrison and Gibaldi (1977)
Lutz et al. (1977)
Fernandez et al. (1977)
Tuey and Matthews (1980) 0.0047
Ramsey and Andersen (1984) 0.015
Fiserova-Bergerova (1985)
Andersen et al . (1987) 0.039
Rat Human
6.48
5.00
6.48
0.03 4.04
4.04
4.04
0.0673
0.0244
6.5
-
0.0940 4.83
6.54
0.0850 5.80
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4.4. CARDIAC OUTPUT DISTRIBUTION
4.4.1. Reference Values
Cardiac output distribution depends on the oxygen demand of the
tissues which increases with physical exercise and decreases with
anesthesia (Astrand, 1983). Blood flow rates, like tissue volumes, can be
independently measured in the laboratory. All blood flow measurements
listed in this section are calculated in liters of blood per hour and
presented as a percentage of total blood flow (cardiac output).
TABLE 4-13 . REFERENCE TISSUE HERFUSION RATES
(fraction of cardiac output)
Liver
Fat
VRG
MS
Mouse
0.25
0.09
0.51
0.15
Rat
0.25
0.09
0.51
0.15
Human
0.26
0.05
0.44
0.25
4.4.2. Documentation of Reference Values
Mice
Wetterlin et al. (1977) reported measurement* of blood flow
distribution in anesthetized NMRI mice of both sexes. Blood flow to the
VRG (brain, heart, kidney, and viscera) accounted for 47.8% of total
cardiac output (brain, 2%; heart, 2.8%; kidney*, 14.6%; and the viscera,
30.2%). Blood flow to the liver measured 8.4 ± 0«8% (arterial blood flow
4-30
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only).
Quintan* et al. (1979) measured the distribution of cardiac output in
BALB/c mice using the radioactive microsphere method. The cardiac output
distribution (%) was expressed in per gram of tissue. We used the organ
weights reported by Crispins (1975) for this particular strain of mice.
When the organ weights were not available for the BALB/c strain, an average
of the reported values was used. Blood flow to the liver was 21%. The
total percentage of blood flow to the VKG was 54% (Brain, 13%; Heart, 6%;
and kidneys, 35%). No values were given for fat or the MB.
Rats
Sasaki and Wagner (1971) reported measurements of blood flow
distribution in unane sthetized rats. Blood flow to the VUG (brain, heart,
kidney, and viscera) accounted for 48.2% of the total cardiac output
(brain, 1.2 ± 0.31%; heart, 2.9 + 0.43%; kidneys, 17.8 + 2.2%; and the
viscera, 26.3%). Blood flow to the liver measured 6.7 ± 1.5% (arterial
blood flow only). Malik et al. (1976) measured the fraction of blood flow
to the liver in 15 conscious Spr ague-Daw ley rats using the reference sample
method. Blood flow was 20.26 + 1.9%. Herd et al. (1968) reported an
approximate blood flow rate of 4 to 5% to adipose tissue in white, male
Hoi tzman rats.
Tsuchiya et al. (1978) determined regional cardiac output distribution
in three strains of unane sthetized rats. Rats included in this study were
five male American Wistar rats (0.473 ± 0.010 kg); six male Wistar-Kyoto
rats (0.447 ± 0.020 kg); and eight male hypertensive, Okamoto-Aoki rats
(0.390 + 0.012 kg). For the three strains of rats, blood flow to the VUG
accounted for 43.5% of total cardiac output. The mean cardiac output
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distributing into the liver (includes portal) was 17% for the three strains
of rats.
Humans
Bradley et al. (1945) reported a human liver blood flow value of 26%.
Jones (1950) reported the same value for liver as unpublished observations.
Leggett and Williams (1985) designated 27% for liver blood flow. Venous
blood accounted for 20% and arterial blood flow. 7.0%.
Our fat blood flow distribution in humans was assigned a value of 5%
in accordance with the recommendation of ICRP (1975). Price et al. (1960)
reported a body fat blood flow fraction of 4.6%. Cowles et al. (1971)
reported a body fat blood flow fraction of 4.5%.
The values for the vessel-rich group are a compilation of measured
values suggested for the particular tissues which make up the group. The
tissues include the brain, heart, kidney, and viscera. The blood flow
distribution of 13% in the brain was supported by measured values reported
by Eety and Schmidt (1945). Jone» (1950), and Chapman and Mitchell (1965).
Brobeck (1979) recommended a slightly higher value of 15%. Blood flow
distribution to the heart in humans was measured at 4.0% by Chapman and
Mitchell (1965) and Brobeck (1979). Jones (1950) suggested a lower value
of 2.6%. For the kidney, a blood flow value of 23% was reported by Smith
(1943) and Jones (1950). Brobeck (1979) recommended a lower value of 20%
and Chapman and Mitchell (1965) suggested 19%. Edwards (1975) suggested an
inter species blood flow of 26% of cardiac output to the kidney. Brobeck
(1979) reported a measured value of 30% for the viscera (includes liver).
Subtracting 26% of blood flow distribution for the liver results in a blood
flow value of 4.0% for the viscera.
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Assam ing a blood flow distribution of 13% to the brain, 4.0% to the
heart, 23% to the kidney and 4.0% to viscera, results in a reference value
of 44% for the VBG. The range in this estimate is 39 to 48%.
Our definition of the muscle group includes the muscle and skin.
Brobeck (1979) reported two values of 15 and 17% for the muscle. Chapman
and Mitchell (1965) reported a higher value of 21%. Blood flow to the skin
was measured at 9.0% (Chapman and Mitchell, 1965) and 10.0% (Brobeck.
1979). Cowles et al. (1971) reported 15.6% blood flow to the muscle and
skin of a 70 kg man.
4.4.3. Values Used in Pharmacokinetic Models
Mice
Bischoff et al. (1971) reported blood flow rates for a 0.022 kg mouse
as follows:
Tissue Fraction
Liver 0.25
Kidney 0.18
Muscle 0.11
A total blood flow value of 0.0044 1/min was used to calculate the blood
flow percentages to the different compartments. Blood flow to the gut
(21%) was assumed to redistribute through the liver.
Dedrick et al. (1973) provided the following blood flow rates for a
0.022 kg mouse:
4-33
-------
Tissue Fraction
Liver 0.41
Heart 0.06
Kidney 0.30
Lean 0.19
Marrow 0.04
Plasma values were converted to blood values based on a hematocrit of 0.40,
and the blood flow rates for the liver, kidney, and gat were scaled in pro-
portion to the data of Bischoff et al. (1971). They also used a total
blood flow value of 0.0044 1/min and assumed the perfusion of blood in the
marrow tissue of mice was equal to that in the rat.
Tuey and Matthews (1980) reported the following blood flow rates for a
0.038 kg mouse :
Tissue Fraction
Liver 0.41
Fat 0.01
Muscle 0.19
Skin 0.02
Blood flow to the muscle and liver were taken from the data of .Dedrick et
al. (1973) and scaled per ml of tissue. Blood flow values for the skin and
adipose tissue compartments were values scaled from a 0.250 kg rat (Lutz et
al., 1977) in proportion to the three-fourths power of the body weight
(Adolph, 1949).
Ramsey and Andersen (1984) reported blood flow distribution in a 0.022
kg mouse to the following tissue compartments:
4-34
-------
Tissue Fraction
Liver 0.37
Fat 0.09
Richly perfused 0.42
Muscle 0.12
Andersen et al. (1987) reported the following blood flow fractions in a
0.038 kg mouse :
Tissue Fraction
Liver 0.24
Fat 0.05
Rapidly perfused 0.52
Slowly perfused 0.19
Rats
Bischoff et al. (1971) reported blood flow measurements in a 0.200 kg
rat as:
Tissue Fraction
Liver 0.31
Kidney 0.24
Muscle 0.14
As with the nice, the measurements were based on a 0.40 heaatocrit and
organ w«ifht-to-body weight relationships formulated by Adolph (1949).
Harrison and Gibaldi (1977) provided blood flow fractions for a 0.360
kg rat as the following:
4-35
-------
Tissue Fraction
Liver 0.33
Kidney 0.27
Skeletal muscle 0.16
Skin, fat, etc. 0.16
Heart 0.08
Total blood flow was 0.0534 1/min. Blood flows for the rat were not scaled
in this study due to differences in the partition coefficients of the
chemical between rats and humans.
Lutz et al. (1977) reported blood flow distribution in a 0.250 kg rat
to the following compartments:
Tissue Fraction
Liver 0.19
Fat 0.05
Muscle 0.09
Skin 0.006
The fraction of blood distributing into the skin is a measurement of
effective blood flow. The actual skin flow rate used in the model was
reduced by 10-fold in order to simulate the behavior of the chemical under
investigation in the skin (Lutz et al., 1977). The blood values were in
close agreement with previously published data.
Fiserova-Bergerova and Hughes (1983) estimated the following blood
flow rates for a 0.250 kg rat:
4-36
-------
Tissue Fraction
Liver 0.29
Fat 0.006
VBG 0.57
Muscle 0.07
Again, as with the fat volume of this model, the blood flow to the fat
appears to be underestimated.
Ramsey and Andersen (1984) reported blood flow distribution in a 0.30
kg rat to the following tissue compartments:
Tissue Fraction
Liver 0.37
Fat 0.09
Richly perfused 0.42
Muscle 0.12
The blood flow to the liver, which represented 37% of cardiac output,
exceeded the more realistic value of 25%. Ramsey and Andersen (1984)
surmised the need to increase the cardiac output was related to the
eztrahepatic metabolism of the chemical under investigation.
Andersen et al. (1987) reported blood flow rates in a 0.233 kg rat for
four tissue compartments:
Tissue Fraction
Liver 0.24
Fat 0.05
Rapidly perfused 0.52
Slowly perfused 0.19
These blood flow fractions were used for the mouse, rat, and hman species.
4-37
-------
Ma pie son (1963) reported the blood flow distribution in a multi-
cdepartmental model for a 70 kg man that included the following fractions:
Tissue Fraction
Adrenals 0.02
Kidneys 0.19
Thyroid 0.01
Gray matter 0.09
Heart 0.04
Other small gland* and organs 0.01
Liver plus portal system 0.25
White matter 0.03
Red marrow 0.02
Muscle 0.09
Skin a) nutritive 0.01
b) shunt 0.20
Non-fat subcutaneous 0.01
Fat 0.03
Total blood flow was 6.48 1/min. Mapleson assumed that the blood flow to
any tissue compartment is a fixed fraction of total cardiac output.
Eger (1963) listed the following perfusion rates for a 70 kg man:
Tissue Fraction
Liver
Fat
VHS
Muscle
VP6
0.26
0.05
0.49
0.18
0.02
Eger included liver in his vessel-rich compartment, and the vessel-poor
compartment included bone and cartilage.
Hanson and Bowers (1967) reported the distribution of blood flow in
human* as 75% to the VBD (included liver and brain), 19.6% for the muscle
4-38
-------
group (includes bone), and 5.4% to fat. These values are used for
simulation of uptake during clinical anesthesia. If liver is designated as
a separate compartment, these values become:
Tissue Fraction
Liver 0.26
Fat 0.05
VBG 0.49
MS 0.20
Bischoff et al. (1971) reported the fraction of blood flow in a 70 kg
man as:
Tissue Fraction
Liver 0.22
Kidney 0.19
Muscle 0.11
Total blood flow was 3.67 1/min. Blood flow to the gut (19%) was assumed
to redistribute through the liver. As with the rodent data, the blood
values are based on a hematocrit of 0.40 and organ weight-to-body weight
relationships.
Dedrick et al. (1972) reported blood flow rates for a 70 kg man
essentially derived froa the work of Ma pie son (1963). The blood flow
fraction for each compartment was:
4-39
-------
Tissue Fraction
Liver
Kidney
Lean
Heart
Harrow
0.36
0.31
0.23
0.06
0.04
Dedrick et al. (1973) reported the following blood flow rates for a 70 kg
man:
Tissue Fraction
Liver
Heart
Kidney
Lean
Harrow
0.36
0.06
0.31
0.23
0.04
Fiserova-Bergerova et al. (1984) used the following blood distribution
fractions in her model simulation of a 70 kg resting man:
Tissue Fraction
Liver 0.23
Fat 0.05
VBG 0.45
Muscle 0.27
A separate compartment for the lung was also included in their model
simulation.
Ramsey and Andersen (1984) reported the distribution of blood flow in
humans as equal to those values given for the mouse and rat:
4-40
-------
Tissue Fraction
Liver 0.37
Fat 0.09
Richly perfused 0.42
Muscle 0.12
Andersen et al. (1987) reported the same blood flow fractions for a 70 kg
man as that of their 0.038 kg mouse and 0.233 kg rat:
Tissue Fraction
Liver 0.24
Fat 0.05
Richly perfused 0.52
Muscle 0.19
4.5. VENTILATION
Ventilation is a cyclic, dynamic process of circulation and exchange
of gases in the lungs that is basic to respiration. Three primary concepts
used to quantify the ventilation process are: minute volume, dead space,
and alveolar ventilation.
Minute Volume
The total volume of air exhaled per minute is known as the minute
volume or total ventilation rate.
Dead Space
Not all inhaled air is available for gas exchange in the alveolar
compartments. The volume of the respiratory tract where .no gas exchange
4-41
-------
occurs is termed the dead space. Anatomical dead space is the internal
volume of the conducting airway from the nose and mouth down to the
alveoli. The physiological dead space includes the anatomical dead space
and, in addition, the conducting airways of the lower respiratory tract
where no significant exchange of oxygen and carbon dioxide between gas and
blood occurs.
Alveolar Ventilation
The traditional definition of alveolar ventilation is the amount of
inspired gas which enters the alveoli per minute. Thus, alveolar
ventilation is defined as:
Alveolar ventilation = minute ventilation - frequency x dead space
Valv = VE - f x VD.
where VD is equal to anatomical dead space.
For the purposes of pharmacokinetic modeling, alveolar ventilation
should be defined as:
* »
Vaiv - VE - f x VD.
where VD is equal to physiological dead space.
4.5.1. Reference Values
Recommendations for reference respiration parameters are given in
Table 4-14. The recommended minute volumes are calculated from power
4-42
-------
functions suggested in Section 5.1. The alveolar ventilation rates are
calculated assuming alveolar ventilation is 67% of minute volumes for mice,
rats, and humans. Physiological dead space is assumed to be 33% in mice,
rats, and humans.
TABLE 4-14. REFERENCE RESPIRATION PARAMETERS
Species
Parameter Mouse Rat Human
Body weight (kg) 0.025 0.25 70.0
Minute volume (1/min) 0.037 0.174 7.5
Alveolar ventilation (1/min) 0.025 0.117 5.0
Physiological dead space (%) 33.0 33.0 33.0
Frequency (breaths/min) 163.0 85.0 15.0
4.5.2. Documentation of Reference Values
The reference minute volume of 0.037 1/min for mice was calculated
using the power function suggested in section 5.1., using a reference mouse
body weight of 0.025 kg. The reference minute volume of 0.174 1/min for
the rat was calculated using the power function suggested for rats in
section 5.1., using a reference rat body weight of 0.25 kg. Alveolar
ventilation reference values for the mouse and the rat were obtained by
taking 67% of the minute volumes for each species. Physiological dead
space was calculated by taking the remaining 33% of minute volume for each
species. The reference minute volume of 7.5 1/min for humans was taken
from ICRP (1975).
4-43
-------
Mice
Minute Volumes
Absolute minute volumes of unanesthetized mice are summarized in Table
4-15.
TABLE 4-15. ABSOLUTE MINUTE VOLUMES OF UNANESTBETIZED MICE
VE
(l/min)
0.024
0.028
0.049
0.052
Range
0.011
0.021
0.035
0.046
- 0.036
- 0.036
- 0.063
- 0.058
Method Ref.
1
2
3
3
Guy ton (1947)
Guy ton (1947)
Schlenker (1985)
Vinegar et al. (1979)
1. Respirograph
2. Head valve
3. PI ethysmograph
Guyton (1947) measured minute volume in 56 unane sthetized mice with an
average body weight of 0.02 kg. Minute volume was 0.024 l/min with a range
of 0.011 to 0.036 l/min. Schi enter (1985) measured minute volume in
unane sthetized Swiss Webster mice with a mean body weight of 0.0304 +
0.0026 kg. Minute volume was 0.0488 ± 0.014 l/min.
Vinegar et al. (1979) measured minute volume in male CD-I mice
weighing 0.027 ± 0.002 kg. Using the body pie thysmograph, minute volume
was measured at 0.052 l/min (range of 0.046 to 0.058 l/min).
Absolute minute volumes of anesthetized mice are summarized in Table
4-16.
4-44
-------
TABLE 4-16. ABSOLUTE MINUTE VOLUMES OF ANESTHETIZED MICE
VE Range
(1/min)
0.021 0.009 - 0.046
0.021 0.019 - 0.022
0.052 0.038 - 0.066
Method
Ref.
2 Crosfill and Widdicombe (1961)
1 Vinegar et al. (1979)
1 VonBucher (1949)
1. PI ethysmograph
2. Tracheal cannul a
A minute volume of 0.021 1/min (range of 0.009 to 0.046 1/min) for a
0.032 kg, anesthetized mouse was reported by Crosf ill and Widdicombe
(1961).
Vinegar et al. (1979) measured minute volume in anesthetized CD-I mice
and recorded a minute volume of 0.021 1/min (range of 0.019 to 0.022
1/min). The minute volume measurement for the anesthetized nice
represented a 40% drop in minute volume from the preanesthetic level.
VonBucher (1949) measured minute volume in 14 anesthetized mice.
Minute volume measured O.OS2 1/min (range of 0.038 to 0.066 1/min).
A summary of relative minute volumes of unanesthetized and
anesthetized mice is presented in Table 4-17 and Table 4-18.
4-45
-------
TABLE 4-17. RELATIVE MINUTE VOLUMES OF DNANESTHETIZED MICE
(1/min-kg)
VE Ranao Method
1.239 0.925 - 1.377 1
1.357 1.420 - 1.708 2
1.612 1.151 - 2.072 3
1.925 1.701 - 2.148 3
Ref.
Guy ton (1947)
Gay ton (1947)
Schlenker (1985)
Vinegar et al. (1979)
1. Respirograph
2. Head valve
3. PIethysmograph.
TABLE 4-18. RELATIVE MINUTE VOLUMES OF ANESTHETIZED MICE
(1/ain-kg)
VE Range Method
0.720 0.240 - 1.720 1
0.777 0.704 - 0.815 2
0.941 0.712 - 1.143 3
2.26 1.652 - 2.869 2
Ref.
Crosfill and Widdicombe (1961)
Vinegar et al. (1979)
Guy ton (1947)
VonBueher (1949)
1. Tracheal cannul a
2. Pie thy tmo graph
3. Tracheal valve
Dead Space
The difficulty in obtaining accurate respiratory measurements in
animals smaller than rats precluded our obtaining sufficient data for mice.
Based on the interspecific consistency in anatomical dead space values, we
can conjecture physiological dead space values are also consistent between
species. Therefore, we are recommending a physiological dead space
4-46
-------
reference value of 33% for mice.
Alveolar Ventilation
We are recommending an alveolar ventilation reference value of 67% of
minute volume in mice based on corresponding data in rats and humans.
Frequency
Measured respiratory frequencies of unanesthetized mice are summarized
in Table 4-19.
TABLE 4-19. RESPIRATORY FREQUENCIES OF UNANESTHETIZED MICE
(br/min)
100
163
176
186
193
213
294*
316*
346*
Range
Ref.
Loosli et al. (1943)
85 - 230 Guyton (1947)
157 - 195 Jaeger and Gearhart (1982)
143 - 226 Jaeger and Gearhart .(1982)
176 - 210 Jaeger and Gearhart (1982)
Crossland et al. (1977)
250 - 338 Jaeger and Gearhart (1982)
275 - 357 Jaeger and Gearhart (1982)
314 - 378 Jaeger and Gearhart (1982)
Unrestrained animals
Measured frequencies of anesthetized mice are summarized in Table 4-
20.
4-47
-------
TABLE 4-20. RESPIRATORY FREQUENCIES OF ANESTHETIZED MICE
1 Range Ref.
(br/min)
109 97 - 123 Crosfill
154
168
198
210
-
and
Widdicombe (1961)
Drorbaugh (1960)
133 - 203 Morrison
- Morr i son
174 - 246 Morrison
80 - 200 Kl oilman
and
and
and
and
El sner
Eisner
Eisner
Radford
(1962)
(1962)
(1962)
(1964)
Rats
Minute
Tables 4-21 through 4-24 summarize the absolute and relative minute
volumes of unanesthetized and anesthetized rats.
Blame (1936) measured minute volume in 23 unanesthetized rats weighing
0.111 kg. Minute volume was 0.228 1/min. In 1943, Blume and Zollner used
the head mask to determine minute volume in 14 unanesthetized rats. Minute
volume measured 0.336 1/min for the 0.229 kg rats.
Guyton (1947) determined the minute volume ia 35 white, unanesthetized
rats (average body weight of 0.113 kg). Minute volume was 0.073 1/min with
a range of 0.050 to 0.101 1/min. Clarkson (1956) reported a minute volume
of 0.100 1/min (range of 0.075 to 0.130 1/min) for a rat (body weight
unavailable). Leong et al . (1964) determined the minute volume for four
groups of male, unane sthetized Wistar rats. Minute volume rose accordingly
with the increase in body weight. For 10 rats weighing 0.211 + 0.007 kg,
4-48
-------
TABLE 4-21. ABSOLUTS MUTOTE VCLUIES OF UNANESTBETIZED RATS
VE Method Ref.
(1/nin)
0.057 4 (»)
0.073 1
0.087 1
0.089 4 (a)
0.094 1
0.100
0.113 1
0.115 3
0.147 4 (a)
0.150 4
0.153 7
0.154 4
0.161 4
0.162 1
0.169 4
0.174 4
0.186 4
0.189 3
0.189 4 (a)
0.194 4 (a)
0.215 2. 4
0.215 6
0.223 4
0.225 1
0.228 1
0.247 4
0.254 4
0.264 4
0.336 5
Bartlett and Tonney (1970)
Gnyton (1947)
Uoag «t al. (1964)
01 ton. aad D«ap»«y (1978)
Davis aad Morris (1953)
Clarkson (1956)
L«oag «t al. (1964)
Palxxk (1969)
Polianiki «t al. (1984)
Tboaas and Morgan (1969)
Natti* (1977)
M»nd«rly (1986)
Dorato »t al. (1983)
Lcoag «t al. (1964)
Laaa «t al. (1982)
Laadsy «t al. (1983)
Oorato « al. (1983)
PalcMk (1969)
Polianski tt al. (1984)
Papp«ah«ia«r (1976)
Ito «t al. (1976)
JUadcrlr «t al. (1979)
Soil en tj aad H«ata (1984)
L.ong «t al. (1964)
Bin* (1936)
TfceBas aad Hortaa (1969)
lUadcrly (1986)
H*nd»rl7 (1986)
Blnac aad Zollncr (1943)
1. Reipiroirtph
2. Oas dilation, FSC
3. Boyle's Lav, FEC
4. Pl«thysaofrapli, (>) bazoB«trio
5. B*ad aask
6. Nonrebr»«tiing valr«s
7. B«ll<7*s puaoBOfraa
4-49
-------
TABLE 4-22. ABSCLDTE MINUTE VCLUJES OF ANESTHETIZED RATS
VE Method
(1/ain)
0.046 3
0.050 3
0,064 3
0.044 3
0.076 6
0.085 3
0.092 3
0.092 3
0.112 3
0.118 3
0.119 1
0.127 3. 5
0.131 3
0.146 1
0.149 3. 5
0.150 3
0.160 2
0.161 3
0.171 1
0.175 3
0.203 3
0.237 3. 4
0.38S 3
££.
Maudarly and Sifford (1978)
Mamderly and Sifford (1978)
EotMztson and Far hi (1965)
TnoBas and Morgan (1969)
Guy ton (1947)
Pal«c«k and Koch ova (1968)
Palaeck «t al. (1967)
Tnoaaa and Morgan (1969)
Paleo.k «t al. (1967)
Palaock and Chralora (1976)
Soneti (1960)
Cbralora »t al. (1974)
Pal»o»k (1969)
Schuti (1960)
Pal«
-------
TABLE 4-23. RELATIVE MINUTE VOLUMES OF UNANESTHETIZED RATS
Relative VE
(l/«in-ki)
0.001
0.142
0.326
0.411
0.540
0.561
0.614
0.646
0.711
0.733
0.755
0.752
0.768
0.773
1.027
1.673
2.054
Method
6
3 (a)
3 (a)
5
3
7
8
1
5
2
1
4
1
3
1
1
1
Ifil-
Bluae tad Zollner (1943)
Bartlett and Tenney (1970)
Olson and Deapsey (1978)
Palecek (1969)
LaBM et al. (1982)
Mauderly et al. (1979)
Nattie (1977)
Guy ton (1947)
Palecek (1969)
Davis and Xosxit (1953)
Leon| et al. (1964)
Ito et al. (1976)
Leong et al. (1964)
Landxy et al. (1983)
L«ong et al. (1964)
Leong et al. (1964)
Blue (1936)
1. Respirograph
2. Respiroeieter
3. Pie thy 00 graph (a) baroaetric
4. Gas dilation, FRC
5. Boyle's Lav. FRC
6. Head »ask
7. Nonzebreathing valves
8. Bellows pneaogzaB
4-51
-------
TABLE 4-24. RELATIVE MINUTE VCLDJES OF ANESTHETIZED RATS
Relative VE
(I/Bin- kg)
0.170
0.201
0.239
0.393
0.415
0.434
0.435
0.457
0.472
0.595
0.600
0.627
0.635
0.637
0.691
0.691
0.707
0.730
0.886
1.630
Method
3
3
3
3
3
3
3
3
3
3
1
2
1
3. 5
6
3
3, 4
1
3
3
Rof.
Mauderly and Sifford (1978)
Robertson and Farhi (1965)
Mauderly and Sifford (1978)
Cavalova et al . (1974)
Palecek and Rochova (1968)
Palecek et al . (1967)
Johanson and Pierce (1971)
Palecek and Chvalova (1976)
Palecek et al. (1967)
Palecek (1969)
Sehuti (1960)
Crosf ill and f iddico.be (1961)
Schutz (1960)
Palecek (1969)
Gay ton (1947)
Diamond and 0' Donne 11 (1977)
Ito et al. (1976)
Schutz (1960)
Palecek (1969)
VonBttcher (1949)
1. Gas meter
2. Passive inflation
3. Pie thy mo graph
4. Gas dilation, FRC
5. Boyle's Law, FRC
6. Tracheal valve
4-52
-------
minute volume was measured at 0.162 + 0.042 1/min. The rats weighing 0.298
± 0.008 kg measured a minute volume of 0.225 ± 0.028 1/min.
Landry et al. (1983) measured minute volume in male Fischer 344 rats
with an average body weight of 0.225 kg. At the optimal breathing capacity
for the rats, minute volume was measured at 0.174 + 0.039 1/min.
Dead Space
Stahl (1967) predicted a dead space value of 0.0004 liters for a 0.250
kg rat. Chvalova and Palecek (1977) measured respiratory dead space in
male Wistar rats as 0.00035 liters. Ward et al. (1983) estimated dead
space in Porton rats as 0.00034 liters. A representative tidal volume for
a 0.250 kg rat is about 0.0015 liters (Crosf ill and Widdicombe, 1961; Leong
et al., 1964; Dor a to et al., 1983). Based on these data, anatomical dead
space in rats is 23% of tidal volume. This number is corroborated by Lai
et al. (1981) who estimated anatomical dead space in male Spr ague-Daw ley
rats to be 22% of tidal volume.
The only study found estimating physiological dead space in rats was
Olson et al. (1978), who estimated dead space in male Spr ague-Daw ley rats
to be 37% of tidal volume. However, our analysis shows that anatomical
dead space values are consistent between species. We conjecture that
physiological dead space should also be consistent between species.
Therefore, we are recommending a physiological dead space reference value
of 33% of tidal volume for rats.
4-53
-------
Alveolar Ventilation
We are recommending an alveolar ventilation reference value of 67% of
minute volume for rats.
Frequency
Respiratory frequencies of unane sthetized and anesthetized rats are
listed in Tables 4-25 and 4-26:
4-54
-------
TABLE 4-25. RESPIRATORY FREQUENCIES OF UNANESTHETIZED RATS
I
(br/min)
60
82
84.9
85
86
91
94.5
102
109
110.2
116.1
119
119
121.4
130
131
134
136
139.3
139
142
142
152
152.5
Range
-
72 - 92
68.3 - 101.5
66 - 114
-
80 - 102
90.8 - 98.2
80 - 124
103 - 115
87.7 - 132.7
103.5 - 128.7
109 - 129
113 - 125
113.7 - 129.1
-
-
-
-
123.5 - 155.1
-
120 - 164
-
-
-
Ref.
McCuicJieon (1951)
Aggarwal et al. (1976)
Bartlett tad Tenney (1970)
Guy ton (1947)
Pappenheiaer (1976)
Palecek (1969)
Ito et »1. (1976)
Mauderly et al . (1979)
Olson and Dempsey (1978)
L«ong ot «1. (1964)
L«on| at tl. (1964)
Palecek (1969)
Nattio (1977)
L«ong at al. (1964)
ThoBas and Morgan (1969)
Maude rly (1986)
Blume and Zollner (1943)
Maude rly (1986)
Leong et al. (1964)
Thomas and Morgan (1969)
Lam et al. (1982)
Maud* rly (1986)
Bluve (1936)
Davis and Morris (1953)
4-55
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TABLE 4-26. RESPIRATORY FREQUENCIES OF ANESTHETIZED RATS
1 Range Ref.
(br/min)
47 - Mauderly and Sifford (1978)
48 - Mauderly and Sifford (1978)
68 - Thomas and Morgan (1969)
69 64.3 - 73.7 Robertson and Farhi (1965)
79 - Thomas and Morgan (1969)
80 - Drorbaugh (1960)
90 81 - 99 Vizek et al. (1975)
92.8 87.1 - 98.5 Chvalova et al. (1974)
96 88.3 - 103.7 Palecek (1969)
97 84 - 126 Crosfill and ffiddicombe (1961)
102 98.9 - 105.1 Ito et al. (1976)
104 93 - 115 Palecek (1969)
108 79 - 137 Johanson and Pierce (1971)
108 98.7 - 117.3 Palecek and Chvalova (1976)
110 - Agostoni et al. (1959)
112 103.3 - 120.7 Palecek (1969)
115 96 - 134 VonBncher (1949)
115 94 - 136 Diamond and 0'Donne 11 (1977)
4-56
-------
Human8
Absolute minute volumes of humans are reported in Table 4-27
TABLE 4-27. ABSOLUTE MINUTE VOLUMES OF HUMANS
VE Ranee
(1/min)
6.02
6.1
6.4
6.5 6.0 - 7.0
7.43 5.8 - 10.3
7.5
7.5
7.7
8.20* 5.38 - 9.14
8.73 4.9 - 12.2
9.0
Ref.
Tobin et al. (1983)
Frostell «t al . (1983)
Crosfill and Widdi combe (1961)
Stahl (1967)
Taylor (1941)
ICRP (1975)
Brobeck (1979)
Frostell et al. (1983)
Bergman (1967)
Guy ton (1947)
Mead (1960)
* Anesthetized
Brobeck (1979) reported & minute volume of 7.5 1/min for a 70.0 kg
man. ICRP (1975) also recommended a 7.5 1/min minute volume for Reference
Man. Taylor (1941) measured minute volume in three male subjects and
reported a minute volume of 7.43 1/min (range of 5.8 to 10.3) in a resting
state. Guy ton (1947) measured minute volume in a 68.5 kg man using the
4-57
-------
oscilloscopic respirograph. Minute volume was 8.73 1/nin (range of 4.9 to
12.2). Crosfill and Widdicombe (1961) reported a minute volume of 6.4 for
a 70 kg man. Bergman (1967) measured a minute volume range of 5.38 to 9.14
1/min in anesthetized subjects breathing 23 to 30% oxygen. Head (1960)
reported an average minute volume measurement of 9.0 1/min for 27 subjects
at rest. Stahl (1967) reported a minute volume range of 6.0 to 7.0 1/min
for a 70 kg man.
Relative minute volumes of humans are summarized in Table 4-28.
TABLE 4-28. RELATIVE MINUTE VOLUMES OF HUMANS
Relative VE Range
Ref.
(1/min* kg)
0.0142
-
0.091
0.1071
0.1071
0.1265
0.0768 - 0.1306 Bergman (1967)
0.0857 - 0.1000 Stahl (1967)
Crosfill and Widdi combe (1961)
Brobeck (1979)
ICRP (1975)
0.0710 - 0.1768 Gnyton (1947)
Dead Space
There are more extensive measurements of both anatomical and
physiological dead space in humans. It is generally accepted that
anatomical dead space as measured by the Bohr equation at normal
ventilation is subject to over-estimation (Chakrabarti et al., 1986). ICRP
(1975) recommended an anatomical dead space value of 0.160 liters and a
tidal volume of 0.75 liters for humans. Based on these data, anatomical
4-58
-------
dead space in humans is 21% of tidal volume.
Nunn and Hill (1960) measured the ratio of physiological dead space to
tidal volume in 12 normal subjects and found the ratio to average 0.32.
Wasserman et al. (1967) found the ratio of physiological dead space to
tidal volume in 10 healthy males to average 0.33 under normal resting
conditions and 0.17 during exercise. Hohsenifar et al. (1985) state that
normal values for the physiological dead space to tidal volume ratio are
0.33 at rest and 0.25 during mild exercise. Based on these data, we are
recommending a physiological dead space reference value for humans of 33%
of tidal volume.
Table 4-29 lists anatomical dead space measurements for humans.
TABLE 4-29. ANATOMICAL DEAD SPACE OF HUMANS
VD Ref.
(liters)
0.130 + 16 « 40 Yr) Tsunoda et al. (1972)
0.136 ± 19 « 40 Yr) Fowler (1949)
0.147 Tatsis et al. (1984)
0.155 ± 24 (> 40 Yr) Fowler (1949)
0.156 ± 16 (> 40 Yr) Tsunoda et al. (1972)
0.160 Svanb«rg (1957)
0.160 ICRP (1975)
4-59
-------
Alveolar Ventilation
Coaroe et al. (1955) recommended an alveolar ventilation rate of 4.2
1/min in a normal, adult male. Head (1960) reported an average alveolar
ventilation rate of 5.2 1/min for 27 subjects at rest. Fenn and Rahn
(1965) list an alveolar ventilation rate of 5.3 1/min. Rackow et al.
(1965) recommended an alveolar ventilation of 5.6 1/min based on two-thirds
of the expiratory minute volume of an anesthetized subject during the first
five minutes of uptake. Salzano et al. (1984) reported alveolar
ventilation rates for divers at rest and during exercise. The resting
values were taken while the divers inspired air containing 50% oxygen. For
subject 1, resting alveolar ventilation was 7.0 ±0.9 1/min; subject 2, 6.8
±0.9 1/min; subject 3, 5.6 ±1.1 1/min; subject 4, 5.4 1/min; and subject
5, 6.6 ± 0.8 1/min.
We are recommending an alveolar ventilation reference value in humans
of 5.0 1/min, which is 67% of our.reference minute volume.
Frequency
Respiratory frequencies of humans are summarized in Table 4-30.
4-60
-------
TABLE 4-30. RESPIRATORY FREQUENCIES OF HUMANS
1 Range Ref.
(br/min)
10.3 8.1 - 12.7 Bergman (1967)
11.7 10.1 - 13.1 Taylor (1941)
14.2 10.5 - 19.3 Guyton (1947)
14.8 - Svanberg (1957)
15 - ICRP (1975)
15.6 - Fowler (1948)
16 - Crosfill and Widdicombe (1961)
11-22 Stahl (1967)
4.5.3. Values Used in Pharaacokinetic Models
Pharmacokine tic models use alveolar ventilation, rather than minute
volume, as an input parameter. Table 4-31 summarizes alveolar ventilation
values that have been used in pharmacokinetic models.
4-61
-------
TABLE 4-31. ALVEOLAR VENTILATION
(1/min)
Source Mouse Rat Human
Mapleson (1963) - - 4.0
Muason and Bowers (1967) - - 4«0
Ramsey and Andersen (1984) 0.0121 0.075 3.83
Fiserova-B. et al. (1984) - - 5.80
Fiserova-Bergerova (1985) - - 5.3
Andersen et al. (1987) 0.039 0.085 5.80
4-62
-------
5. SCALING
Many of the physiological parameters used in pharmacokine tic modeling
are directly correlated to the body weight of the particular organism.
These physiological parameters generally vary with the body weight
according to a power function expressed as:
y = a BW b
where y is a physiological parameter of interest, and a and b are constants
(Fiserova-Bergerova and Hughes, 1983). If the constant b equals one, the
physiological parameter y correlates directly with body weight. If the
constant b equals two-thirds, the parameter y correlates with surface area.
This formula was taken from the classical paper of Adolph (1949). which is
generally recognized as the definitive source on the quantitative
relationship between body weight and the physiological parameters.
The most desirable method of obtaining the physiological parameters
used in a pharmacokine tic model is direct measurement. When such values
are not available, necessary biological parameters for an untested species
can be obtained through scaling. Scaling is defined as the orderly
variation of anatomic and physiologic properties with body weights (Adolph,
1949). Animal scale-up is possible because both large and small animals
are physiologically similar. With only minor exceptions, the mechanisms of
absorption, renal excretion, distribution, and storage are relatively
similar in all species of animals, including humans (Fiserova-Bergerova and
Hughes, 1983). The concept of using body weight scaling in pharmacokine tic
modeling was introduced by Dedrick (Dedrick, 1973; Dedrick and Bischoff,
1980). Many of the anatomical and physiological parameters can be
5-1
-------
correlated among species as exponential functions of body weight:
Property
Kidney weight
Brain weight
Heart weight
Lungs weight
Liver weight
Stomach and intestines weight
Blood weight
Constant
(a)
.0212
.081
.0066
.0124
.082
.112
.055
Exponent
(b)
0.85
0.70
0.98
0.99
0.87
0.94
0.99
Adapted from Adolph (1949).
5.1. CARDIAC OUTPUT
Cardiac output is defined as the volume of blood pumped by each
ventricle of the heart per minute. Inter species scaling of cardiac output
is known to depend on the 0.75 power of body weight (Stahl. 1967; White et
al., 1968; Holt et al., 1968; Takezawa et al.. 1980). In fact, there is
considerable evidence that both cardiac output and minute volume scale
across species with the three-fourths power of body weight (Kleiber, 1961;
Holt et al., 1968; Schmidt-Nielsen, 1970). It can therefore be assumed
that intraspecies extrapolations of cardiac output and minute volume should
also scale with the three-fourths power of body weight (Andersen et al.,
1987).
Correlations based on empirical observations of inter species scaling
of cardiac output have found the following power functions:
5-2
-------
TABLE 5-1. CARDIAC OUTPUT
(1/min)
Constant
(a)
0.102
0.162
0.166
0.187
Exponent
(b)
0.9988
0.76
0.78
0.81 .
Ref.
Patterson et
White et al.
Holt et al. (
Stahl (1967)
al. (1965)
(1968)
1968)
It is known that these power functions slightly underpredict cardiac
output in small mammals (Guyton, 1947).
Empirical measurements of cardiac output in mice, rats, and humans
follow.
5.1.1. Mice
Empirical measurements of cardiac output of mice are shown in Table
5-2.
TABLE 5-2. SCALING CARDIAC OUTPUT OF MICE
£0
(l/min)
0.0110*
0.0118*
0.0160
BW CO/BW 0.75 Ref.
(kg)
0.025 0.175
0.0272 0.176
0.0225 0.275
Gjedde et al. (1980)
Wetterlin et al . (1979)
Blizard et al. (1971)
* Anesthetized
5-3
-------
Using the estimate of cardiac output in unane sthetized mice (Blizard and
Welty, 1971) and assuming cardiac output is related to the 0.75 power of
body weight results in the following power function, where cardiac output
is expressed in liters per minute (1/min) and body weight in kilograms
(kg):
CO = 0.275 (BW) 0-75
5.1.2. Rats
Empirical measurements of cardiac output of unane sthetized rats are
shown in Table 5-3.
TABLE 5-3. SCALING CARDIAC OUTPUT OF UNANESTHETIZED RATS
co
(1/min)
0
0
0
0
0
0
0
.0730
.0918
.1010
.1107
.1167
.1193
.1340
BW
(kg)
0
0
0
0
0
0
0
.113
.319
.355
.447
.390
.473
.512
CO/BW 0.75 Ref.
0
0
0
0
0
0
0
.375
.216
.220
.203
.237
.209
.221
Guy ton (1947)
Popov ic and Kent
Jan sky and Hart
Tsuehiya
Tsuchiya
Tsuchiya
Coleman
et al.
et al.
et al.
(1974)
(1964)
(1968).
(1978)
(1978)
(1978)
Assuming that cardiac output is related to the 0.75 power of body
weight and taking the geometric mean of the ratios of CO/BW 0.75 flom Table
5-3, results in the following power function for cardiac output in
5-4
-------
unanesthetized rats, where cardiac output is expressed in 1/min and body
weight in kg:
CO = 0.235 (BW) °-75
Measurements of absolute cardiac output of anesthetized rats are listed in
Table 5-4.
TABLE 5-4. SCALING CARDIAC OUTPUT OF ANESTHETIZED RATS
£0
(l/min)
0.027
0.040
0.047
0.047
0.063
0.070
0.095
0.120
BW
(kg)
0.213
0.213
0.190
0.180
0.304
0.394
0.412
0.490
CO/BW 0.75
0.086
0.128
0.163
0.170
0.154
0.141
0.185
0.205
Ref.
Walsh et al. (1976)
Walsh et al. (1976)
Blood et al. (1950)
Clarkson (1956)
Chiu (1974)
Ac kern a nn et al. (1980)
Lin et al. (1970)
Holt et al. (1968)
As SUB ing that cardiac output is related to the 0.75 power of body
weight and taking the geometric mean of the ratios of CO/BW °»?5 from Table
5-4. results in the following power function for cardiac output in
anesthetized rats, where cardiac output is expressed in 1/min and body
weight in kg:
5-5
-------
CO = 0.150 (BW) 0-75
5.1.3. Humans
Measurements of absolute cardiac output of humans are summarized in
Table 5-5.
TABLE 5-5. SCALING ABSOLUTE CARDIAC OUTPUT OF HUMANS
CO
(1/min)
4.60
4.88
5.20
5.21
5.30
5.51
5.60
5.73
6.00
6.00
6.21
6.30
6.49
BW
(kg)
73
63
-
69
72
68
70
73
75
75
72
70
68
CO/BW 0.75 Ref.
0.184
0.218
-
0.218
0.214
0.233
0.231
0.229
0.235
0.235
0.251
0.260
0.274
Shaw et al. (1985)
Starr et al. (1940)
Frostell et al. (1983)
Astrand et al. (1964)
Reeves et al. (1961)
Cournand et al. (1945)
Guyton (1971)
Starr et al. (1940)
Johnson et al. (1968)
Stead et al. (1945)
Tanner (1949)
Cowles et al. (1971)
Brandf onbrener et al. (1955)
The best summaries of data for cardiac output in humans appear to be
Tanner (1949), Brandfonbrener et al. (1955). and Cowles et al. (1971).
These studies indicate that cardiac output decreases with age but is about
5-6
-------
6.2 to 6.5 1/min for men between the ages of 20 to 30 years old. Thus, we
are recomaending a reference cardiac output of 6.2 1/min.
5.2. MINUTE VENTILATION
Ventilation is a cyclic process of circulation and exchange of gases
in the lungs that is basic to respiration. Total ventilation or minute
volume is defined as the volume of air exhaled per minute. Minute volume
has been correlated with the three-fourths power of body weight:
TABLE 5-6. MINUTE VOLU1E
(1/min)
Constant
(a)
0.332
0.373
0.379
Exponent
(b)
0.74
0.75
0.80
Ref
Adolph (1949)
Guyton (1947)
Stahl (1967)
For mice, minute volume was shown to scale, as was cardiac output, with a
mass exponent of 0.75.
Empirical measurements of minute volume in mice, rats, and humans
follow.
5.2.1. Mice
A summary of empirical studies of unane sthetized mice for which both
minute volume and body weight were available is provided in Table 5-7.
5-7
-------
TABLE 5-7. SCALING MINUTE VCLDHES OF ONANESTHETIZED MICE
VE
(l/min)
0.0245
0.0281
0.0489
0.0521
BW
(kg)
0.0198
0.0207
0.0304
0.0270
VE/BW 0.7J
0.464
0.515
0.672
0.782
* Ref.
Guyton (1947)
Guyton (1947)
Sehlenker (1985)
Vinegar et al. (1979)
Assuming minute volume is related to the 0.75 power of body weight and
*
taking the geometric mean of the ratios of VE/BW °-75 from Table 5-7
results in the following power function of minute volume in unane sthetized
mice, where minute volume is expressed in 1/min and body weight in kg:
VE = 0.595 (BW) 0-75
Measurements of minute volumes of anesthetized mice are listed in Table 5-
8.
TABLE 5-8. SCALING MINUTE VOLUICS OF ANESTHETIZED MICE
VE
(l/min)
0
0
0
.021
.021
.052
BW
(kg)
0
0
0
.032
.027
.023
VE/BW 0-75 Ref.
0
0
0
.278
.315
.881
Crosf ill
and
Vinegar et al
VonBucher
Widdi combe
. (1979)
(1961)
(1949)
5-8
-------
As Sinn ing minute volume is related to the 0.75 power of body weight and
taking the geometric mean of the ratios of VE/BW °-75 from Table 5-8,
results in the following power function of minute volume in anesthetized
mice, where minute volume is expressed in 1/min and body weight in kg:
VE - 0.426 (BW) 0-75
5.2.2. Rats
Table 5-9 presents data on minute volumes of unane sthetized rats.
5-9
-------
TABLE 5-9. SCALING MINUTE VCLU1ES OF UNANESTHETIZED RATS
VE M VE/BW
(l/ain) (kj)
0.037 0.400 0.113
0.073 0.113 0.375
0.087 0.052 0.799
0.089 0.273 0.236
0.096 0.131 0.441
0.113 0.110 0.592
0.115 0.280 0.299
0.147 0.294 0.368
0.153 0.249 0.434
0.154 0.219 0.481
0.161 0.218 0.505
0.162 0.211 0.520
0.169 0.313 0.404
0.174 0.225 0.533
0.186 0.248 0.529
0.189 0.266 0.510
0.189 0.296 0.471
0.215 0.222 0.665
0.215 0.383 0.442
0.225 0.298 0.558
0.228 0.111 1.186
0.254 0.255 0.708
0.264 0.219 0.825
0.336 0.229 1.015
Bietlatt tad Tenney (197C)
Go?ton (1947)
L.OBI «t al. (1964)
01 ton and De»pt»y (1978)
Davis and Morris (1953)
L*ong «t al. (1964)
Ptlec«k (1969)
Polianski »t al. (1984)
Natti* (1977)
Maodasly (1986)
Dor«to «t al. (1983)
L.onj «t al. (1964)
LUB «t al. (1982)
Landry »t al. (1983)
Dor a to «t al. (1983)
Pal«o»k (1969)
Poliaaaki ct al. (1984)
Ito «t al. (1976)
Jteiuterljr »t al. (1979)
Loonj it al. (1964)
Bloa. (1936)
Ma«d«rl7 (1986)
M»ud.rly (1986)
Bloa« and Zollacr (1943)
5-10
-------
Assuming that minute volume is related to the 0.75 power of body
weight and taking the geometric mean of the ratios of V£/BW 0.75 flom Table
5-9, results in the following power function for minute volume in
unane sthetized rats, where minute volume is expressed in 1/min and body
weight in kg:
VE - 0.492 (BW)0.75
Table 5-10 lists minute volumes of anesthetized rats.
5-11
-------
TABLE 5-10. SCALING MINUTE VCLDJES OF ANESTHETIZED RATS
VE
(I/Bin)
0,046
0.050
0.064
0.076
0.085
0.092
0.112
0.118
0.119
0.127
0.131
0.146
0.149
0.160
0.161
0.171
0.175
0.203
0.237
0.388
BW
(kg)
0.271
0.209
0.318
0.110
0.205
0.195
0.258
0.258
0.160
0.323
0.220
0.240
0.234
0.280
0.233
0.285
0.402
0.229
0.335
0.238
VE/BW °-75
0.123
0.162
0.151
0.398
0.279
0.314
0.309
0.326
0.470
0.296
0.408
0.426
0.443
0.416
0.480
0.438
0.347
0.613
0.538
1.139
Ref.
Mauderly et al. (1978)
Mauderly et al. (1978)
Robertson and Far hi (1965)
Guyton (1947)
Palecek and Rochova (1968)
Palecek et al. (1967)
Palecek et al. (1967)
Palecek et al. (1976)
Sehutz (1960)
Chvalova et al. (1974)
Palecek (1969)
Sehatz (1960)
Palecek (1969)
Crosf ill and Widdi combe (1961)
Diamond et al. (1977)
Sehutz (1960)
J chanson et al. (1971)
Palecek (1969)
Ito et al. (1976)
VonBucher (1949)
Assuming that minute volume is related to the 0.75 power of body
weight and taking the geometric mean of the ratios of VE/BW 0.15 from Table
5-12
-------
5-10, results in the following power function for minute volume in
anesthetized rats, where minute volume is expressed in 1/min and body
weight in kg:
VE = 0.359 (BW) 0.75
5.2.3. Humans
Minute volumes of humans are reported in Table 5-11.
VE
(1/min)
6.02
6.4
7.43
7.5
7.5
8.73
6.5
TABLE 5-11. SCALING MINUTE VOLUMES OF HUMANS
Bf VE/BW
(kg)
70
-
70
70
0.265
-
0.310
0.310
68.5 0.367
70 0.269
Tobin et al . (1983)
Crosf ill and Widdicombe (1961)
Taylor (1941)
ICRP (1975)
Brobeck (1979)
Guyton (1947)
Stahl (1967)
5-13
-------
APPENDIX A
This appendix provides a limited review of the literature on partition
coefficients for use in pharmacokine tic modeling. A partition coefficient
is an expression of the solubility of a chemical. It is used to describe
the partitioning of a given chemical between air and blood, and blood and
tissues. Partition coefficients can be determined in the laboratory using
a vial equilibration technique (Sato and Nakaj ima, 1979).
6-1
-------
COEFFICIENT FOR MCE, fcAIS, AND HUKAKS AS REPORTED IN THE UIERATURE.
LIVES FA1 nuSCU KIDNEY PLASM LUN6
CMfniCAL
SPECIES Oil/ROOD
OIL
BLOOD
VESSEL RICH VESSEL POOR SERUIt REF
Acetone
Acetone
Acrtont
Acttone
Acrtont
Acetylene
Acrtylrnt
Acrylonitrilt
Allylbtnirnt
Allylbtnirnt
Argon
tail Mr
Ininr
iMIIIt
InfMr
Irnme
Irnimr
Irnmr
Imint
Inline
Itnitnt
Imtme
ltni»t
tVoMk«oi(
-------
CHEHICAL
Cryofluorut
Cutcnt
Cuitnt
Cycloouui
Cyclohciut
Cycloproput
Cycloarount
Cyclopropui
Crclopropui
Cytlofroput
CfdoprofUi
Cytloyrouu
8icklarofemitM, i-
licklorobMim, -
lickloroktflitm, o-
luklgrobnint, o-
licklorotthut 1,2-
Sicklorotthtnt, ,|-
licklorottkut, ,1-
licklorotthut, ,1-
ticklarotthut, ,1-
luklorottkut, ,1-
(7, tuklorottkut, ,1-
1 luklorottkut, ,2-
L'J ftcklorottkut, ,2-
licklorottkut, ,2-
lUklorottkut, ,2-
McklorMtkut, ,2-
fctHofMthylwe, cit-1,2-
hcklorotthylint, cit-1,2-
licklorMtkylMt, trui-1,2-
licklorottkylMt, trtat-1,2-
fccklorotthylwie, trui-1,2-
licklorofrofui, 1,2-
tickloroproptit, 1,2-
hitkyl itktr
liitkyl itlxr
Urtkyl ttkrr
dttkyl itlxr
tittkyl ttkir
kiftkyl tlkir
httkyl ttktr
lirthyl ttkir
Mitkfl tttoni
Mitkyl kttMii
li
-------
CHEKICAL
[nl lur *ne
f nf lur tat
tnf lurtnt
Eif lunnr
Enf lurtnt
Enflurtnt
Ethtnc
Elhtne
Ethine
Elhtnr
Ethyl chloridt
Ethyl chloridt
Ethyl chloridt
Ethyl forutt
Ethyl octint
Ethylbtnitnt
Ethylbtnitnt
Ethylbtnitnt
Ethyltnt
Ethyltfit
Fluorocirbon II
Fluorocirbon II
Fluorocirbon 113
fluorocirbon ||<
Fluorocirhoi 12
Fluoroctrbon 12
Fluroitit
Fluroitflt
fluroitnt
FluroiMt
fluroitflt
Hilothm
Hilothint
Htlothut
Htlothut
HtUthut
Htlothut
Hllothut
Htlothut
Htlothtne
Htftut, -
H*tuont, 2-
HtitUuorotthut
Mnut, n-
luflurine
Iwfluruf
luflurint
IsoMurint
luf lurtnt
Krypton
SPECIES
huiin
huitn
huiin
huitn
huiin
rtt
huiu
huiin
huiu
MMII
huiu
huitn
huiu
huiu
huiu
huiin
huiu
hmu
huiu
huiu
huiu
huiu
huiu
huiu
hum
huiu
huiu
huun
huiu
huiu
huiu
huiu
huiin
huiu
huiu
huMi
huiu
huiu
huMJI
rjt
huiu
huiin
OUIt
huiin
huiu
huiu
huiin
huiu
rit
Dull
OIL/HLOOD OIL
...
...
...
...
...
...
...
...
...
II
24
...
...
37*1
133
...
27
...
32
5
3
...
...
...
...
...
...
...
4S2«/-20.0
4791
0.13
!44*/-4.f
...
...
...
0.50
BLOOD LIVES FST
2.0 2.3
1.7
l.» -- 70
1.3-2.2
l.t
2.o
0.10
O.OB
0.05
l.t
1.9
44.4
74.4
28.4
32.1
28.4»/-|.7
0.15 O.tS
0.14 5.t
...
0.87
...
...
0.15
1.4 34
1.4
1.5
1.3
1.4
2.4 155
l.t
2.4
2.S
2.S 40. 9
l.t-2.8
2.8
2.3-2.7
3.4
1. 9 1 /-O.I IO.BtM.0 J85»/-1J.«
Iff
0.80«/-O.OB 5.2«/-0.7 I04*/-l«.»
1.3
1.4 48
1.5
1.4-1.4
1.4
~~" --- ---
COdllNUfD.
rWSCLE KIDNEt PLASnA LUNG VESSEL RICH VESSEL POOH SCRUB HE
2
2
1
2
2
2
2
2
2
3
1.2 4
2
2.3 5
2
2
2
2
II
1.0 1.0 1.0
0.1
...
0.8
0.2
0.2
...
...
...
...
...
...
3.5 2.5 1.0
... ...
...
12.5»/-0.4 8.t»/-l.2 2.5»/-0.2
5.0«/-0.» 3.0*M.I l.0*/-0.07
2
1
2
2
2
3
-------
tn
CHEfllCAL
Hethinf
Htthoiyf lunnt
Httkoiyllurint
Httkoiyflurmt
Htthoiyflurmt
Hrthoiyflurinr
Htthoiyflurmt
Itctkoiyflurmt
Httkyl chloridt
Httkyl ckloridt
Httnyl chloridt
Httkyl ttkyl kttont
Httkyl ttkyl kttont
flttkyl liobutyl kttont
ttkyl itofcityl kttont
Ittkyl i-kutyl kttont
Httkyl i-tutyl ktto»
llttkyl itityl kttont
Hrtkyl propyl kttont
Httkyl propyl kttont
HttkylcyclofHtiflt
HrtkyltM ckloridt
Httkyl Mt ckloridt
ttkylnt ckloridt
flrtkyltut chloridt
ttkylMt ckloridt
RttkylMi ckloridt
ftttkyltflt ckloridt
Hrtkyl tut ckloridt
Httkylhfiint, 3
rtkylptfltttt, 2-
IWhylptMiM, 3-
IhMCkloraiitmtiit
Intrift*
totroMthint
fetrMt oiidt
fetroui otidt
lltroM and!
(btrmt oiidl
totrnt oiidt
fntiit, -
h*yl ttktr
fr^ylitniMf
frt»ylktnit«t
Snot 1 unit
StyrtM
Styrtnt
Styrtnt
Styrtut
Styrtnt
- -
SPECIES
huiin
huun
huiin
huiin
huiin
huiin
huiin
rit
hum
hunii
huiin
h«Mn
kuitn
huiin
hulUI
huiin
hum
hutn
hum
hiiin
hum
huiui
kutin
kuiin
ku»m
hum
huiin
kutn
rit
hum
hum
hutm
hum
Mil
hum
hum
kutrn
hum
kum
MUM
huiu
h»«m
kum
hum
hum
hum
hum
hu»n
huiin
rit
OIL/BLOOD
---
---
...
...
...
...
...
---
...
...
1.3
10
...
...
13
34
4.2
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
208
...
...
105
OIL
...
...
---
---
...
...
...
...
8
243
...
924
...
...
...
424
202«/-1I.O
...
l52»/-5
75
152
...
3II»/-24.0
!03*/-7.3
HBt/-8.0
3743«/-»7
0.072
...
...
...
1.4
47«/-2.3
9775
53
...
...
4100
4114
jloj
CONTINUED.
BLOOD LIVER FAI IWSCLE HONE*
0.041
12.9
11-17
12.3
II --- 6/0
13.2
14-17
1
0.8
...
O.g
202
202»/-IO
«/-!!
to
!27»/-7
l««/-24
I50«/-I2
150
0. Bit/ -0.08 7.8«/-I.O I74«/-IO.O 5.0»/-0.8 4.7*/-|.l
7.0
9,7»/-0.4
7.0
5.3-4.4
9.7
9.4
12.8
I.]«H).I I0.4«/-l.l 277«/-24.0 I0.8W-0.7 7.3»/-2.l
0.4I»/-4.07 4.5«/-l.l 87»/-7.0 2.t«/-0.9 2.0»/-l.l
0.43«/-0.07 4.9«/-I.O 102»/-8.0 3.fl«/-0.8 2.5«/-I.O
30.8»/-l.9
...
42J
0.44
0.47 2.3 1.13
0.42
0.47 1.4
O.J8*/-O.Ofl 2.l»/'0.9 J9.4«/-2.4 0.7«/-0.4 0.4«/-0.3
8.8
47.0«/-2.4
47 ---
0.4
44
5I.9«/-2.0
IT
ii
j2
40 2.7 50 1.0
PLASHA LUNb VESSEL RICH VESSEL POOR SERlffl REf
,
2
2
2
1
2
2
2
O.fl 4
1.7 5
2
2
... ... ||
>.- -
--- 2
2
11
11
11
2
1.7»/-0.04 7
2
- I0
,.5 4
II | 5
2
2
_____ __ ___ _ 9
2
7
O.B*/-0.04 7
0.9»/-0.04 7
10
j
... ... ... . 2
2
1.04 1,0 4
2
1
3
0.5«/-0.03 7
... ... 2
II
2
2
... ... ... 2
11
2
5.7 8
-------
CHCIUCAl
Sulfur h»i«f luor lit
Sultur lunflLuridr
Svllur ktiifluwidt
Sulfur htiifluondt
UtrichlnroftkMt, 1, ,1,2-
!r(r«hlofo»llij«e, , ,1,2-
IttrichlorMthut, , ,1,2-
lttrichloro*tk«», , ,1,2-
Iftruhlorortkut, , ,2,2-
lttr«chlwMtkiM, , ,2,2-
lttruhloro*tk«nc, , ,2,2-
l«tr«klorottkwt, , ,2,2-
IrtrMhlorMtkylnt
!( rtchl or o* Inline
IttrKhlorulkirlnt
ItUichlorottkfltM
TttrunlorottkjlMt
UtrMklvMtkyiiii
IkioMtkaivflirMC
lolMM
lolltM
III MM
Til MM
111 MM
III MM
1*1 MM
111 MM
1*1 MM
III MM
Til MM
IrickiorMtkiM, 1, , -
IrtctlorottkMC, 1, , -
IricklorMtktM, 1, , -
1ricUwM4kMe, 1, , -
IricklorMtkm, t, , -
TricklirwtlMM, 1, ,2-
TrictlirMtkuf, I, ,2-
TnrtlorMUm, 1, ,2-
IricUvMtlMM, 1, ,2-
IricklarMtkM*, I, ,2-
IricklffoctkfltM
tricklorMtbyliM
VicklirMtk|l«M
1ridtiWMtkvl«M
TncM«Mtk;l«M
trirtlvortkrlmi
Trirtlor«tth|lfi«
Iricklorortkylnt
ImklarMtkylMt
SCECIES
huun
tiuitn
kuitn
Mil It
lluiin
hunn
hunn
hunn
huiM
huitn
hMU
huiu
kuiu
kuaui
kuu
k«iM
kUMfl
kvttn
k»M
hum
kuw
kuin
kuin
kulM
ku«
kuMn
kUM
hUM
r«t
rit
hum
hum
kuin
hum
kuw
hutin
kuin
k.UM
kuiin
httAM
kUM
huu
kUM
kiun
nuiin
hunn
hunn
huain
hum
OIL/BLOOD Oil
...
0.30
4J06
...
43«4»M?5
I32I1«/-303
---
1110
13211
UI7
4M
I1I7»/-I2»
7320
»4
1380
1471
...
...
...
...
...
354»/-20
...
I3»
334
380
...
2273«/-237
2273
7I«
...
...
718
718«/-8
---
""" ---
CONllNUED.
BLOOD LIVER FA! rlUSCLE MONEt PLASHA
0.00«
0.0064
0.0053
JO
72.6
J0.4*/-2.1
I2I.4«/-5.I
73
141
220
121
13.1
».l
II. t
32
I3.U/-I.I
».|
l£
I3.4«/-I.7
13.4
7.3-13.1
U.j
l2f6.M»/-tl.32
14.;
13.6
14.24-84.5*
I4.34-J3.53
IS.2
t.4
l.«
3.3«/-0.4
1.4
7
j.j
56
44.2
38.4«/-4.4
44,2
31.4
t.»2«/-0.4J 474.40«M4.08
».6
«.0 600
1.5
1.1
1.5
».5«/-0.6
».i
3.»-|0.2
LUN6 VESSEL RICH VESSEL POOR SERUn REF
2
2
2
3
2
78.2 4
10
10
2
2
5
2
2
2
2
5
JO
4
2
II
2
2
2
1
T.
2
13
13
2
2
3.4 4
10
2
]
2
5
37.1 4
10
2
2
12
2
|
1
2
2
2
10
6
2
-------
CONTINUED.
CHEHICAL SPECIES OIL/BLOOD OIL BLOOD LIVER fAI HUSO.E KIDNEY PLASflA
If uMarotUyltne fit --- --- 26 --- ---
Irichlorotthyltnt rit --- 25.B2«/-I.70 I.6H/-0.37 25.5HM.Ofl 0.43«/-0.01 l.35«/-0.48
Irichlorotthyltnt rit - 7.4
If ichlorotthyltnt, 1,1,2- huiin 220 --- - 15
Ii ichlorotthyltnc, 1,1,2- huiin --- --- 9.5
lrHluoro-2-cklorocthint, 1,1,1- hu««i 24 1.4
Itnon hiiMD 0.14 1.3
Itnon h««n - 1.9 0.14
Itnon IOUM 2.0
lyltnt liuturt) kutM 4030 42.1
lyltnt, - hull* 146 24.4»/-0.9
lyltnt, i- kuitn 3142 26.4
lyltnt, - hiuu 24.50-30.98 ~
lyltflt, - huitn 3404.47*/-I1B.7
lyltnt, i- (wain 21.0
lyltdt, - kktu 27.12-30.47
lyltftt, o- hiMD 4340 31.1
lyltnt, o- ku*M 140 3I.M/-2.J
lyltnt, p- kuau 3414 37.4
lyltnt, p- hum J4.2
lyltnt, p- hum 98 37.4*/-3.5
I
I. ftin|old, A. 1174. Antfth. Anilg. 55141:513-515.
2. Finfo»*-l»r(tra»i, V. 1983. Itodtlmi o< Inhilition Eipoiurt to Viporit Uptikt, Bittrikutim Hid ElUimtin 1:14-20. loci Riton fL:CK Prm.
3. Killer, K. *.; Piton, H. 1. li.j Stitk E. 1.) Suth, R. A. 1972. Anntkmol. 34(41:331-331.
4. Nor«M, A.; »Uck. A.; Itkhir, 0. R. 1170. Ann. Occuf. Hyj. 13:211-233.
5. tofjtfl, A.; 81 act, A.) Itilth, H.| Idckir, D. R. 1172. lit. i. Appl. I^Ut. Itat. 23i283-211.
4. Pipptr, E. H.i Mill, R. J., (di. 1143. Uptik* ind Ciitribitiw e< AtMtkttic Agjnts, pp. 71, 77. MM forki IkSrM-Hili leek Co.
7. Ptffetllix, I.; lru««ont, S.j Ctrttti, D.; hVintllt, t. 1183. Ir. I. Ind. ted. 42il42-167.
8. RiiitY, i. C.i Andtrioi, H. t. 1184. Toiicol. Appl. Pkiri. 73:139-173.
9. Site, .; Fujioirt, 1,; ktkijiu, T. 1174. jpn. 1. Ud. H*iith 16:30-31.
16. Site, .; lUkijiu, T. 1171. Arck. En.irofl. Htilth 34:41-73.
11 S«to | lUktjiM T 1171. Ir. J. Ind. tod. Ui231-234.
12. Sato, .; Hikiiiu, 1.; Fu|iwr«, ?.; Duriyui, N. 1177. Ir. J. Ind. tod. 34:36-41.
13. Site, ., ti it. 1172. Jpn. i. Ud. Htilth 14:3-1.
LUNG VESSEL RICH VESSEL POOR SERUN Rff
2
I.03«/-O.I7 12
2
5
5.1 4
2
2
2
II
2
13
9
2
13
2
11
2
2
11
-------
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