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Evaluation of a pulmonary clearance and accumulation model for gases
Evaluation
of a Pulmonary
Accumulation
SARFARAZ
Model
for
Clearance
and
Gases
NIAZI
Department of Pharmacy, Colkge ofPharmacy, lJnioersi@ of Illinois Medical Center, Chicago, Illinois 60612
Communicated
by W. R. Adey
ABSTRACT Various including
factors
affecting
the role of lung
the transpulmonary surfactants.
transport
Predicted
values
model for gases are discussed, of pulmonary
clearance
were
found to be in reasonable agreement with experimental values. An equation is proposed for the volumes of distribution and accumulation of gases as a function of time.
INTRODUCTION The uptake and distribution characteristics of gaseous compounds have been extensively elaborated [l-4], and the mathematical models describing them range from simple single compartment lung models to multicompartmental AV shunt and diffusion weighted models [5,6]. In this paper, a simple model of pulmonary clearance is evaluated in the light of recent experimental data. Also, a general equation for the volume of distribution is proposed, and the use of this parameter is described in evaluating the accumulation of various gaseous compounds in the body.
PULMONARY
CLEARANCE
MODEL
Upon inhalation, a gas distributes evenly in various parts of the lungs, and it has been shown [7] that diffusion within alveoli is not a significant limiting process in the exchange of gases through the lungs, since the diffusion coefficient of a gas in a gas mixture is of the order of about 200,000 times that of a gas in liquid or tissue [S]. The diffusional equilibrium of gas within the blood capillary is described MATHEMATICAL
0 American
Elsevier
BIOSCIENCES Publishing
21, 169-G%
Company,
(1975)
Inc., 1975
169
SARFARAZ
170
NIAZI
bY ]91 m
Fraction
of equilibrium
= l-
4c
(DK&r/@)
c
RN2
N=I
J,(X) = 0 [J,(X) being the where R, is the Nth root of the equation coefficient, zero-order Bessel function of the first kind], D is the diffusion and b is the capillary radius. It has been shown [IO] that ignoring the longitudinal diffusion, 90 per cent equilibration for nitrogen can be achieved in about 0.01 set in a 4 CL radius capillary. It can therefore be assumed without introducing significant error
in
the
model
that
intracapillary
blood
tension. Although the diffusion of a gas within the capillary can be easily subjected to mathematical
maintains
a uniform
gas
lung and within a blood treatment and collective
conclusions drawn, the diffusion of a gas between alveoli and capillary blood offers problems in the selection of a suitable model, since the actual mechanism of gas transport across alveoli is not yet clearly understood. According to the diffusion model [7], the pulmonary membrane is assumed to have similar solubility properties to those of whole blood, and the diffusing capacity D, is a function of the molecular weight and solubility a. The unit of D, is (ml/min)/mmHg. The equilibration across the pulmonary membrane can, therefore, be expressed as [7] Fraction
of equilibrium
= 1 - e pxt
(2)
where
K=
(B-WD, V@
(3)
and B = barometric 47 = vapor
pressure
V’, = pulmonary The D, value for carbon to be 55 ml/min mmHg,
pressure of water at 37°C.
capillary
blood
volume
(~70
ml)
monoxide has been experimentally determined [7] and can be used to calculate D, for other gases
TRANSPULMONARY
using the following
TRANSPORT
MODEL
171
FOR GASES
relationship:
D MX -=D MC0
a,
(4)
Qo
The solubility (Y,defined here as partition coefficient between blood and air for various gases, has been reported in the literature for anesthetic gases [ 1 l] and fluorocarbon aerosol propellants in various species [ 121. Table 1 reports the calculated diffusion capacity for these gases [Eq. (5)] and the time required for 99 per cent equilibration between pulmonary blood and alveoli. It is apparent that if the proposed model holds, the diffusion across the pulmonary membrane does not offer any significant resistance to the transfer of gases between the lung and blood compartments, since blood spends about 0.75 set in the capillaries equilibrating with alveoli. The diffusion model of transpulmonary transport does not however, take into account the dynamic nature of the surface properties of the pulmonary membrane due to presence of lung surfactants [13]. Upon exhalation, the surface tension of the pulmonary membrane drops sharply, and the role of this hysteresis loop [ 131 in the transport process has been explored [ 141; it may involve solubilization and coacervation.
Paramaters Compound
(Human)
TABLE 1 For Pulmonary
[(ml/mi$ Ether Chloroform Ethyl chloride Halothane Vinyl ether ’ Acetylene Cyclopropane Nitrous oxide Propylene Ethylene Fluorocarbon 11 Fluorocarbon 12 Fluorocarbon 114
15.00 7.30 2.50 2.30 1.50 0.82 0.47 0.47 0.22 0.14 0.94 0.28 0.26
Clearance
D
(Y
28191.6 10820.2 5052.7 2648.8 2898.3 2600.3 1172.65 1145.5 548.9 427.7 1296.1 411.6 321.5
Model 10.99
mmHg)
]
F,
( psec) 14.43 18.28 13.42 23.55 14.02 8.55 10.86 11.13 10.86 8.89 19.66 18.46 21.95
0.050 0.098 0.243 0.258 0.348 0.495 0.629 0.629 0.787 0.855 0.461 0.741 0.757
172
SARFARAZ
The model
seems
attractive
in view of the hydrophobic
nature
NIAZI
of various
gaseous compounds listed in Table 1 and their rapid transport [7] across an aqueous barrier (pulmonary membrane). No mathematical model can, however, be proposed to describe the role of lung surfactants, in view of the inadequate data available at this time. It can, however, be speculated that the presence of surface active agents at the pulmonary membrane-blood barrier will enhance the uptake process, since not only the solubility of many non-polar compounds but also their diffusion coefficients, increase considerably in the presence of surface active compounds [ 151. In short, from above discussion, it can be assumed without introducing significant error that in each cycle the blood passing through lungs is completely
equilibrated
tion Fe for uptake the mass law
with alveolar
or pulmonary
F, =
contents,
clearance Amount
Total
equilibra-
according
to
lost to lungs
amount
CLv.4 = C,V,+QC,
and the fractional can be expressed
reaching
(6)
lungs
(7)
’
where CL and C, are the equilibrium concentrations in the lung and blood, and Va and Q are the volume of air exchanged per minute and the cardiac output. Since the ratio of C, to CL is expressed as a solubility, Eq. (7) can be written as [16]:
An average value of 1.25 is chosen values for various gases reported represent the equilibration of blood The simplified model described
for Q/ VA ratio [ 171, and the clearance in Table 1. Conversely, these values during uptake or inhalation. above can be tested if the value for
pulmonary clearance is obtained pharmacokinetically. pharmacokinetically defined as [ 181 Clearance=
E
=
Do
The
,
clearance
is
(9)
$ 4/a, ,=I where AUC is the total area under the blood concentration-time curve, and A, and ai are the ith intercept and exponent respectively in an N compartment model. For those gaseous compounds which are exclusively eliminated through
the lungs,
(e.g.,
some
fluorocarbon
aerosol
propellants
[19]), the
TRANSPULMONARY
TRANSPORT
MODEL
173
FOR GASES
total body clearance will be equal to the pulmonary clearance (PC). The fraction cleared in each cycle through the lungs can then be written as
Do
F_PC_
=
Q
Q
(10)
$ Ai/ai
i=l
The dose, Do, represents the amount absorbed through the lungs. It is, however, more convenient to administer the dose quantitatively in solution form through the veins [20], in which case a significant amount will be eliminated through the lungs, and thus the term Do will have to be corrected for this loss: D”=D,?v(l-Fe),
where Dfv is the intravenous gives
(11)
dose. Substitution 1
F, =
_
of Eq. (11) into Eq. (10)
.
(12)
QZ’= Ala,
Recently, Niazi and Chiou [20] reported the pulmonary clearance following intravenous administration of the three most commonly used fluorocarbon aerosol propellants in dogs. Figure 1 shows the regression of
0. 2
0.4
0. 6
T:!FORFTICAL
FIG. 1. Relationship carbon aerosol propellants
between theoretical in dogs.
0.8
1.0
F,
and experimental
values
of Fe for fluoro-
174
SARFARAZ
NIAZI
experimental data [Eq. (12)] on theoretical values [Eq. (S)]. It is clear that in spite of large biological variation of ventilation and cardiac output and the assumptions involved in the clearance model, a reasonably good approximation to uptake and pulmonary clearance can be made based on the solubility
characteristics
VOLUME
of these compounds.
OF DISTRIBUTION
AND
ACCUMULATION
The degree of accumulation of gaseous compounds (e.g., anesthetics following multiple inhalations) can be approximated volume
of distribution
calculations.
The volume
of distribution
volatile through
Vd has been
defined as the proportionality constant between amount of drug in the body and blood concentration, and is often dealt with as constant and thus defined in terms of the nature of the compartmental mode1 [21]. More appropriately, this term should be defined as a function of time, since in a multicompartmental drug disposition mode1 the distribution occurs as a function of time: D’xf
Vd=N
(13)
in the body where f is the fraction of drug remaining as fraction of total area under blood concentrationtime
and can be expressed curve:
(14)
and hence
Substitution
Eq. (13) can be written
of Eq. (9) leads
as
to
Clearance
X EyeI
Vd = C;“= ,AieFaz’
5 e Pa,{ a,
(16)
TRANSPULMONARY
The amount of time:
TRANSPORT
retained
MODEL
in the body (As) can then be expressed as a function
A, = Clearance x
cN
A. Le-4r. a; i=l
This equation is independent of the complexities model and the linearity of the disposition kinetics. For compounds which are exclusively eliminated
A,=PCx
N
of the compartmental through the lungs,
A. (18)
’
1+1.25a
following
(17)
2 r;‘e-“’ i=l ’
= Q x~~_,(A,/ai)e-“’
and by analogy,
175
FOR GASES
multiple
(19)
dosing [22],
A = Q xZ;“,,(Ai/ui)(l -ciA’q) B 1+ 1.25a
(20)
where j = number
of doses,
At = dosing interval. The values for the disposition rate constants a, have been reported for various gases [ 1,201. The corrected values for the extrapolated intercepts A, after multiple dosing can be obtained by following equation [22]:
A,=
Ai(app)(l - e-A’q) 1 _ e-jAra,
’
(21)
are the intercepts following the last dose, whereAi(app) REFERENCES
1 E. M. Papper and R. J. Kitz, Uptake and Distribution of Anesthetic Agents, McGrawHill, New York,
1963.
176
SARFARAZ
2
R. K. Stoelting and E. I. Eger, II, the effects of ventilation and anesthetic on recovery from anesthesia, Anesfhesiology 30, 29&296 (1969).
3
S. S. Kety, Theory
5
solubility
and application of exchange of inert gas at the lungs and tissues, (1951). W. W. Mapleson, The uptake and distribution of inhaled anesthetics-a broad picture, in Proc. 4th World Gong. An&h. (1970), pp. 375-381. Pharmacol.
4
NIAZI
Rev. 3, l-41
D. S. Riggs, The Mathematical Approach Wilkins, Baltimore, 1963, p. 324.
to Physiological
Problems,
Williams
and
H. D. Landahl, in Uptake and Distribution of Anesthefic Agents, McGraw-Hill, New York, 1963, pp. 191-214. -I R. E. Foster, Exchange of gases between alveolar air and pulmonary capillary blood: pulmonary diffusing capacity, Physiof. Rec. 37 (1957), 391452. 8 D. S. Dittmer and R. M. Grebe, Handbook of Respiration, Wright Air Dev. Cent., Ohio, 1958. 9 J. Crank, Mathematics of Diffusion, Clarendon, Oxford, 1969. 10 R. E. Foster, II, in Uptake and Distribution of Anesthetic Agents, McGraw-Hill, New York, 1963, pp. 21-27. 11 A. Goldstein, L. Aronow and S. M. Kalman, Principles of Drug Action, Harper & Row, New York, 1969. of Fluorocarbon Aerosol Propellants, Ph.D. dissertation, 12 S. Niazi, Pharmacokinetics University of Illinois Medical Center, 1974. 13 R. E. Pattle, in Advances in Respiratory Physiology, Edward Arnold, London, 1966, pp. 83-105. 14 B. Ecanow, R. C. Balagot and V. Santelices, Possible role of alveolar surfactants in the uptake of inhaled gases, Nature 215, 14OCLl402 (1967). Soiubilization by Surface-Acfiue 15 P. H. Elworthy, A. T. Florence and C. B. Macfarlane, 6
16 17 18 19 20 21 22
Agenfs, Chapman and Hall, London, 1968. J. W. Severinghouse, in Uptake and Distribution New York, 1963, pp. 59-71.
of Anesfhefic
agents,
McGraw-Hill,
W. S. Spector, Handbook of Biological Dafa, W. B. Saunders, Philadelphia, 1956. D. Perrier and M. Gibaldi, Drug clearance in multicompartment systems, Can. J. Pharm. Sci 9, 11-13 (1974). P. J. Cox, L. J. King and D. V. Parke, A study of the possible metabolism of trichloromonofluoromethane, Biochem. J. 130, 136140 (1972). S. Niazi and W. L. Chiou, Pharmacokinetics of fluorocarbon aerosol propellants, presented at A.Ph.A. Convention, Chicago, August 1974. S. Riegelman, J. Loo and M. Rowland, Concept of volume of distribution and possible errors in evaluation of this parameter, J. Pharm. Sci. 57, 128-133 (1968). J. M. van Rossum and A. H. M. Tomey, Multicompartmental kinetics and accumulation plateau, Arch. Inf. Pharmacodyn. 188, 20&203 (1970).
of a Pulmonary
Accumulation
SARFARAZ
Model
for
Clearance
and
Gases
NIAZI
Department of Pharmacy, Colkge ofPharmacy, lJnioersi@ of Illinois Medical Center, Chicago, Illinois 60612
Communicated
by W. R. Adey
ABSTRACT Various including
factors
affecting
the role of lung
the transpulmonary surfactants.
transport
Predicted
values
model for gases are discussed, of pulmonary
clearance
were
found to be in reasonable agreement with experimental values. An equation is proposed for the volumes of distribution and accumulation of gases as a function of time.
INTRODUCTION The uptake and distribution characteristics of gaseous compounds have been extensively elaborated [l-4], and the mathematical models describing them range from simple single compartment lung models to multicompartmental AV shunt and diffusion weighted models [5,6]. In this paper, a simple model of pulmonary clearance is evaluated in the light of recent experimental data. Also, a general equation for the volume of distribution is proposed, and the use of this parameter is described in evaluating the accumulation of various gaseous compounds in the body.
PULMONARY
CLEARANCE
MODEL
Upon inhalation, a gas distributes evenly in various parts of the lungs, and it has been shown [7] that diffusion within alveoli is not a significant limiting process in the exchange of gases through the lungs, since the diffusion coefficient of a gas in a gas mixture is of the order of about 200,000 times that of a gas in liquid or tissue [S]. The diffusional equilibrium of gas within the blood capillary is described MATHEMATICAL
0 American
Elsevier
BIOSCIENCES Publishing
21, 169-G%
Company,
(1975)
Inc., 1975
169
SARFARAZ
170
NIAZI
bY ]91 m
Fraction
of equilibrium
= l-
4c
(DK&r/@)
c
RN2
N=I
J,(X) = 0 [J,(X) being the where R, is the Nth root of the equation coefficient, zero-order Bessel function of the first kind], D is the diffusion and b is the capillary radius. It has been shown [IO] that ignoring the longitudinal diffusion, 90 per cent equilibration for nitrogen can be achieved in about 0.01 set in a 4 CL radius capillary. It can therefore be assumed without introducing significant error
in
the
model
that
intracapillary
blood
tension. Although the diffusion of a gas within the capillary can be easily subjected to mathematical
maintains
a uniform
gas
lung and within a blood treatment and collective
conclusions drawn, the diffusion of a gas between alveoli and capillary blood offers problems in the selection of a suitable model, since the actual mechanism of gas transport across alveoli is not yet clearly understood. According to the diffusion model [7], the pulmonary membrane is assumed to have similar solubility properties to those of whole blood, and the diffusing capacity D, is a function of the molecular weight and solubility a. The unit of D, is (ml/min)/mmHg. The equilibration across the pulmonary membrane can, therefore, be expressed as [7] Fraction
of equilibrium
= 1 - e pxt
(2)
where
K=
(B-WD, V@
(3)
and B = barometric 47 = vapor
pressure
V’, = pulmonary The D, value for carbon to be 55 ml/min mmHg,
pressure of water at 37°C.
capillary
blood
volume
(~70
ml)
monoxide has been experimentally determined [7] and can be used to calculate D, for other gases
TRANSPULMONARY
using the following
TRANSPORT
MODEL
171
FOR GASES
relationship:
D MX -=D MC0
a,
(4)
Qo
The solubility (Y,defined here as partition coefficient between blood and air for various gases, has been reported in the literature for anesthetic gases [ 1 l] and fluorocarbon aerosol propellants in various species [ 121. Table 1 reports the calculated diffusion capacity for these gases [Eq. (5)] and the time required for 99 per cent equilibration between pulmonary blood and alveoli. It is apparent that if the proposed model holds, the diffusion across the pulmonary membrane does not offer any significant resistance to the transfer of gases between the lung and blood compartments, since blood spends about 0.75 set in the capillaries equilibrating with alveoli. The diffusion model of transpulmonary transport does not however, take into account the dynamic nature of the surface properties of the pulmonary membrane due to presence of lung surfactants [13]. Upon exhalation, the surface tension of the pulmonary membrane drops sharply, and the role of this hysteresis loop [ 131 in the transport process has been explored [ 141; it may involve solubilization and coacervation.
Paramaters Compound
(Human)
TABLE 1 For Pulmonary
[(ml/mi$ Ether Chloroform Ethyl chloride Halothane Vinyl ether ’ Acetylene Cyclopropane Nitrous oxide Propylene Ethylene Fluorocarbon 11 Fluorocarbon 12 Fluorocarbon 114
15.00 7.30 2.50 2.30 1.50 0.82 0.47 0.47 0.22 0.14 0.94 0.28 0.26
Clearance
D
(Y
28191.6 10820.2 5052.7 2648.8 2898.3 2600.3 1172.65 1145.5 548.9 427.7 1296.1 411.6 321.5
Model 10.99
mmHg)
]
F,
( psec) 14.43 18.28 13.42 23.55 14.02 8.55 10.86 11.13 10.86 8.89 19.66 18.46 21.95
0.050 0.098 0.243 0.258 0.348 0.495 0.629 0.629 0.787 0.855 0.461 0.741 0.757
172
SARFARAZ
The model
seems
attractive
in view of the hydrophobic
nature
NIAZI
of various
gaseous compounds listed in Table 1 and their rapid transport [7] across an aqueous barrier (pulmonary membrane). No mathematical model can, however, be proposed to describe the role of lung surfactants, in view of the inadequate data available at this time. It can, however, be speculated that the presence of surface active agents at the pulmonary membrane-blood barrier will enhance the uptake process, since not only the solubility of many non-polar compounds but also their diffusion coefficients, increase considerably in the presence of surface active compounds [ 151. In short, from above discussion, it can be assumed without introducing significant error that in each cycle the blood passing through lungs is completely
equilibrated
tion Fe for uptake the mass law
with alveolar
or pulmonary
F, =
contents,
clearance Amount
Total
equilibra-
according
to
lost to lungs
amount
CLv.4 = C,V,+QC,
and the fractional can be expressed
reaching
(6)
lungs
(7)
’
where CL and C, are the equilibrium concentrations in the lung and blood, and Va and Q are the volume of air exchanged per minute and the cardiac output. Since the ratio of C, to CL is expressed as a solubility, Eq. (7) can be written as [16]:
An average value of 1.25 is chosen values for various gases reported represent the equilibration of blood The simplified model described
for Q/ VA ratio [ 171, and the clearance in Table 1. Conversely, these values during uptake or inhalation. above can be tested if the value for
pulmonary clearance is obtained pharmacokinetically. pharmacokinetically defined as [ 181 Clearance=
E
=
Do
The
,
clearance
is
(9)
$ 4/a, ,=I where AUC is the total area under the blood concentration-time curve, and A, and ai are the ith intercept and exponent respectively in an N compartment model. For those gaseous compounds which are exclusively eliminated through
the lungs,
(e.g.,
some
fluorocarbon
aerosol
propellants
[19]), the
TRANSPULMONARY
TRANSPORT
MODEL
173
FOR GASES
total body clearance will be equal to the pulmonary clearance (PC). The fraction cleared in each cycle through the lungs can then be written as
Do
F_PC_
=
Q
Q
(10)
$ Ai/ai
i=l
The dose, Do, represents the amount absorbed through the lungs. It is, however, more convenient to administer the dose quantitatively in solution form through the veins [20], in which case a significant amount will be eliminated through the lungs, and thus the term Do will have to be corrected for this loss: D”=D,?v(l-Fe),
where Dfv is the intravenous gives
(11)
dose. Substitution 1
F, =
_
of Eq. (11) into Eq. (10)
.
(12)
QZ’= Ala,
Recently, Niazi and Chiou [20] reported the pulmonary clearance following intravenous administration of the three most commonly used fluorocarbon aerosol propellants in dogs. Figure 1 shows the regression of
0. 2
0.4
0. 6
T:!FORFTICAL
FIG. 1. Relationship carbon aerosol propellants
between theoretical in dogs.
0.8
1.0
F,
and experimental
values
of Fe for fluoro-
174
SARFARAZ
NIAZI
experimental data [Eq. (12)] on theoretical values [Eq. (S)]. It is clear that in spite of large biological variation of ventilation and cardiac output and the assumptions involved in the clearance model, a reasonably good approximation to uptake and pulmonary clearance can be made based on the solubility
characteristics
VOLUME
of these compounds.
OF DISTRIBUTION
AND
ACCUMULATION
The degree of accumulation of gaseous compounds (e.g., anesthetics following multiple inhalations) can be approximated volume
of distribution
calculations.
The volume
of distribution
volatile through
Vd has been
defined as the proportionality constant between amount of drug in the body and blood concentration, and is often dealt with as constant and thus defined in terms of the nature of the compartmental mode1 [21]. More appropriately, this term should be defined as a function of time, since in a multicompartmental drug disposition mode1 the distribution occurs as a function of time: D’xf
Vd=N
(13)
in the body where f is the fraction of drug remaining as fraction of total area under blood concentrationtime
and can be expressed curve:
(14)
and hence
Substitution
Eq. (13) can be written
of Eq. (9) leads
as
to
Clearance
X EyeI
Vd = C;“= ,AieFaz’
5 e Pa,{ a,
(16)
TRANSPULMONARY
The amount of time:
TRANSPORT
retained
MODEL
in the body (As) can then be expressed as a function
A, = Clearance x
cN
A. Le-4r. a; i=l
This equation is independent of the complexities model and the linearity of the disposition kinetics. For compounds which are exclusively eliminated
A,=PCx
N
of the compartmental through the lungs,
A. (18)
’
1+1.25a
following
(17)
2 r;‘e-“’ i=l ’
= Q x~~_,(A,/ai)e-“’
and by analogy,
175
FOR GASES
multiple
(19)
dosing [22],
A = Q xZ;“,,(Ai/ui)(l -ciA’q) B 1+ 1.25a
(20)
where j = number
of doses,
At = dosing interval. The values for the disposition rate constants a, have been reported for various gases [ 1,201. The corrected values for the extrapolated intercepts A, after multiple dosing can be obtained by following equation [22]:
A,=
Ai(app)(l - e-A’q) 1 _ e-jAra,
’
(21)
are the intercepts following the last dose, whereAi(app) REFERENCES
1 E. M. Papper and R. J. Kitz, Uptake and Distribution of Anesthetic Agents, McGrawHill, New York,
1963.
176
SARFARAZ
2
R. K. Stoelting and E. I. Eger, II, the effects of ventilation and anesthetic on recovery from anesthesia, Anesfhesiology 30, 29&296 (1969).
3
S. S. Kety, Theory
5
solubility
and application of exchange of inert gas at the lungs and tissues, (1951). W. W. Mapleson, The uptake and distribution of inhaled anesthetics-a broad picture, in Proc. 4th World Gong. An&h. (1970), pp. 375-381. Pharmacol.
4
NIAZI
Rev. 3, l-41
D. S. Riggs, The Mathematical Approach Wilkins, Baltimore, 1963, p. 324.
to Physiological
Problems,
Williams
and
H. D. Landahl, in Uptake and Distribution of Anesthefic Agents, McGraw-Hill, New York, 1963, pp. 191-214. -I R. E. Foster, Exchange of gases between alveolar air and pulmonary capillary blood: pulmonary diffusing capacity, Physiof. Rec. 37 (1957), 391452. 8 D. S. Dittmer and R. M. Grebe, Handbook of Respiration, Wright Air Dev. Cent., Ohio, 1958. 9 J. Crank, Mathematics of Diffusion, Clarendon, Oxford, 1969. 10 R. E. Foster, II, in Uptake and Distribution of Anesthetic Agents, McGraw-Hill, New York, 1963, pp. 21-27. 11 A. Goldstein, L. Aronow and S. M. Kalman, Principles of Drug Action, Harper & Row, New York, 1969. of Fluorocarbon Aerosol Propellants, Ph.D. dissertation, 12 S. Niazi, Pharmacokinetics University of Illinois Medical Center, 1974. 13 R. E. Pattle, in Advances in Respiratory Physiology, Edward Arnold, London, 1966, pp. 83-105. 14 B. Ecanow, R. C. Balagot and V. Santelices, Possible role of alveolar surfactants in the uptake of inhaled gases, Nature 215, 14OCLl402 (1967). Soiubilization by Surface-Acfiue 15 P. H. Elworthy, A. T. Florence and C. B. Macfarlane, 6
16 17 18 19 20 21 22
Agenfs, Chapman and Hall, London, 1968. J. W. Severinghouse, in Uptake and Distribution New York, 1963, pp. 59-71.
of Anesfhefic
agents,
McGraw-Hill,
W. S. Spector, Handbook of Biological Dafa, W. B. Saunders, Philadelphia, 1956. D. Perrier and M. Gibaldi, Drug clearance in multicompartment systems, Can. J. Pharm. Sci 9, 11-13 (1974). P. J. Cox, L. J. King and D. V. Parke, A study of the possible metabolism of trichloromonofluoromethane, Biochem. J. 130, 136140 (1972). S. Niazi and W. L. Chiou, Pharmacokinetics of fluorocarbon aerosol propellants, presented at A.Ph.A. Convention, Chicago, August 1974. S. Riegelman, J. Loo and M. Rowland, Concept of volume of distribution and possible errors in evaluation of this parameter, J. Pharm. Sci. 57, 128-133 (1968). J. M. van Rossum and A. H. M. Tomey, Multicompartmental kinetics and accumulation plateau, Arch. Inf. Pharmacodyn. 188, 20&203 (1970).