J. theor. Biol.

(1970) 29, 63-83

Generalized Solution to Linear, Two-compartment, Open Model for Drug Distribution

KENNETH

B.

BISCHOFF?

AND

ROBERT

L.

DEDRVX

Biomedical Engineering and Instrumentation Branch, Division of Research Services, Nafiottal Itwtitutes of Health, Public Health Service, U.S. Deparfment oj Health, Education and Welfare. Bethesda, A4ar~*fand 200 14, U.S. A. (Received 16 Jwtc 1969, and it! re\,i.sed,form 29 December 1969) A two-compartment model based on a well-perfused viscera region and a poorly perfused tissue region can simulate many of the general features of drug distribution kinetics such as concentration peaks that may occur at short times. A thorough discussion and mathematical analysis of the model are presented. The equations are expressed in terms of a number of dimensionless variables for generality, solved for drug administration in the form of any arbitrary form of injection and illustrated for the cases of constant intravenous infusion, a short intravenous injection, and absorption by the gut. Solutions are presented in graphical form, and a number of limiting cases are derived. It is shown that the volume of distribution and the spccilic elimination rate constant are not generally equal to those obtained from a onecompartment analysis, and a simple criterion is developed to test the validity of the single-compartment approximation. The dimensionless solutions may be used directly to predict concentration as a function of time in either compartment if the relevant parameters are known a priori. Alternatively, a simple graphical technique is described to aid in parameter estimation by matching a dimensionless model curve with a dimensional plot of plasma concentration vs. time. 1. Introduction There are many criteria for choosing an appropriate pharmacokinetic model based on physiological necessity and mathematical convenience. A onecompartment model is often useful, but it cannot efTectively describe events such as concentration peaks occurring at short times (5 to 1 hour). Toxicity and other pharmacologic effects associated with these peaks thus cannot he correlated. A two-compartment model based on a well-perfused central or viscera compartment and a poorly perfused tissue compartment can i- Permanent address: School of Chemical Engineering, Cornell University, Ithaca, New York, U.S.A.
63

64

Ii.

H.

BISCHOF~

ANI)

R.

1..

I)EDRICK

simulate these events more accurately and can be more useful, even though additional complexity is required. Riegelman, Loo & Rowland (196&h) have recently argued for the use of a two-compartment model. In certain special cases, such as high lipid solubility, other specific compartments may also be called for. Many of the general features of drug distribution events, however, can be displayed by a two-compartment linear model, and ;I thorough discussion of its properties is therefore appropriate. 2. Mathematical The primary Statement of Two-compartment Mode!

equations are:
+ Mg(t) - kc, (1)

where VI and V, are the central and tissue region volumes, C, and C2 are the corresponding concentrations, Q, is the intercompartment transport parameter, k is the total clearance by metabolism and excretion, M is the amount of drug absorbed (which may not always be equal to the dose, D), and g(t) is a function describing the pattern of injection or absorption. The function g(t) can take many forms, the most common being: i.v. impulse; g(r) = S(t) i.v. step or constant infusion; g(t) = (R/M) U(r) G.I. impulse; g(t) = /<, e-OU(t) where s(t) z Dirac delta function (34 (3b.l

(3cJ

R E infusion rate, moljmin

C/(f) z unit step function lc, z gut absorption constant, min- The G.I. absorption term is that ordinarily used (e.g. Kriiger-Thiemer, 1966) and is based on unidirectional transport from the G.I. compartment to blood. Graphical presentation of solutions to the differential equations (1) and (2) will be presented for each of the three injection functions, equations (3a, b, c), as well as analytical methods for more general cases. The parameter, K. represents the equilibrium distribution ratio between the tissue and blood concentrations. When the mass balances are written in terms of free concentrations, it, of course, has a value of unity. Often, however, it is more convenient to usetotal (free plus bound) concentrations in the balances, and then K # 1; the solutions to equations (1) and (2) could apply to either case.

TWO-COMPARTMENT

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65

3. General Solutions to Equations The basic two-compartment model has been used previously by some early workers such as Teorell (1937), Dominguez (1935), Morales & Smith (1948), and others; more recent discussions are given by Riggs (1963), Wagner & Northam (1967), Riegelman, Loo & Rowland (1968a,b), Wagner (1968), Wagner, Novak, Leslie & Metzler (1968) and Wagner & Metzler (1969). Although the above authors presented several sets of curves, a thorough general computational evaluation has not been performed: this will be presented here. For sake of generality, it is useful to introduce certain dimensionless variables, as defined below:

YlP

GUI +KI/,)
M

YZP E

CZ(Vl +KVz)
KM

Pulse solutions

(54

Cl YiS = c :2
Yzs Kc,

Step solutions

(5b)

where C, 3 R/k = final equilibrium concentration. Then, equations (1) to (3) take the forms: ~1 dy, -l+a -dT =
1 __
d~)-Y,+XY2-Y,)

l+a

dyz -

dt

= &Y,

-Yz)

i.v. impulse i.v. step G.I. impulse where

(8a) (8b)
(8~)

For any arbitrary form of g(z), the superposition theorem for linear differential equations (see, e.g. Himmelblau & Bischoff, 1968, or Kaplan, T.B. 5

66

K.

B.

BISCHOFF

AND

R.

L.

DEDRICK

1962) provides the general impulse response, or convolution

solution:

YI(T)dg(~)[(YlP)i,,,(~-~)l = dz =[ SC7 [(Y - z) lP)i.v.(T)] dT ~~(5)A(1 e-A(ta)T = +u) dz s~(+)*JI~(T)

where the (Y,~)~,~, in equations (9) and (10) is the solution equations (6) and (7) with g(z) = h(r): (y ),, ,=1-J! [r2+;1(l+u)]er2-[r,+A(l+u)]e
IP lb

(9) (10) (11)

found from

r2 - r

with

\![I +~(1+c+JZ-41a 2C! Thus, any g(z) can be substituted into equation (9) or found from an integration. It is easily shown that the given in the above references of constant infusion, G.I. recovered from equations (9) to (11). One particular case of interest, as an example, would of the form:

r(:) = - +[l+i.(l+a)]&R 2M R= I+u i

(13a)

(10) and the solution other standard cases pulse, etc., are easily be multiple injections (14)

g(z) 6(~)pi: 6(z AJ = + i=l

where p = maintenance dose/initial dose Ai = (dimensionless) dosage interval, which may not be equal. For this case, equations (9) or (10) immediately yield: ;;;$,i = e-r,L-;i
-I

[r,+jL(l

+a)]

1 +p i eCrzAi
i=l 1

erzr er}.

-[r,+&l+cc)]

[l +pi$le-rlA]

(15a)

For the special case of equal dosage intervals, Ai = iA, the equation (15a) becomes :
,!:iC$=!+;* cl L rz-rl {[r,+A(l+a)] -iI-gTA[ 1 +p emAwl] er2 erlT}.

-[r,+A(l+cl)]

[i+pe<ii,;!]

(15b)

TWO-COMPARTMENT

OPEN

MODEL

67

Equation (15b) can be viewed as an extension to two compartments of similar results for one compartment by Dost (1953), Wiegand, Buddenhagen & Endicott (1963), and Kri.iger-Thiemer (1966). These authors wrote the solution in terms of the time during a dosage interval, 5, = t - nA:
h&J) = l+c2 L u 12-r1 {[r2+it(l+a)] -[r,+A(l+c!)] [enrzA+p s] $$:I

ezr,l
erln}.

[e+p

(15c)

It can be shown (by methods similar to those used below) that equation (15~) reduces to the results of the above authors if two compartments are reduced to one (A -+ co). Extensions using multiple G.I. doses could be found in a similar fashion, as recently presented by Wagner & Metzler (1969). It should be emphasized again, however, that equations (9) to (11) are not limited to even such inputs as unequal dose intervals or constant infusion of finite duration as considered by Wagner et al. (1968), but can be used for an? input function, g(z). There is a further application of the general equations (9) to (1 I) that may be of use if a therapeutic criterion on the central concentration, J.~(T). is known [or on y2(z)] from the biological effect desired as discussed by Wagner (1968). For example, a common criterion is the maintenance of a drug concentration at the site of action constant above a critical therapeutic limit over some time interval. Given this criterion, one could then use the mathematical methods of optimization theory (e.g. Wilde & Beightler, 1967) to derive the most appropriate form of g(r). In other words, one could determine that g(z) which gives the closest approach to the desired drug concentration criterion. Clinically, one might not use this optimal g(T) dosage regimen-it might well be approximated by a predetermined series of injections suggested by the form of equation (14). However, the optimal g(7) results could indicate the best that could be done and also serve as a guide for an effective practical dosage regimen. For the special case of a one-compartment model, constant desired concentration, and g(z) being limited to the form of a series of equally spaced injections, the analytical results derived from equation (15) can lead directly to the best regimen without recourse to formal optimization theory. Kriiger-Thiemer (1966) has presented a thorough analysis of this so-called plateau effect. If, however, g(z) is not restricted to a series of equally spaced doses, a much wider range of possibilities exists for devising efficient dosage regimens. Also, criteria other than a constant concentration could be accommodated by these methods. Other aspects, such as toxicity limits, could also be included as criteria, although not much is quantitatively

68

K.

B.

BISCHOFF

AND

R.

L.

DEDRICK

known about these at present. Optimization concepts will not be considered in further detail here-they have been suggested merely as one possible valuable application for the general equations (9) to (11). 4. Computational Results A series of computations were performed based upon the analytical solutions derived above. General dimensionless plots are useful here, since detailed evaluations for specific two-compartment cases are not then required for each new case-all such solutions are contained in the figures. Several other features of these models first require attention. Consider the dimensionless parameters: a, 1, [. For physiologically meaningful cases, the ratio of volumes, a, is bounded, and it is shown in Appendix A that generally 0.1 < a < 0.5. In principle, A, the ratio of the flow between regions to the elimination constant, can take on any value over the range (0, co). Finally, although the ratio of G.I. absorption to elimination, i, might have a complete range of values, it is usually greater than I.0 and often exceeds 10 (Wagner, 1967).

0.8 SO.6 0.4

(b) 0.8 -

@2

0.4

0.6

0.8

I.0

I.2

l-4

I.6

I8

20

FIG. 1. Response to iv. continuous ment 2.

infusion, (I = @3. (a) Compartment

1, (b) compart-

TWO-COMPARTMENT

OPEN

MODEL

69

Figure 1 shows the results for the step (or constant infusion) solution. As can be expected, the concentrations rise from zero to unity in a somewhat exponential fashion. It can be shown that as I + co. yIs = yzs-+ l-e- (16) as illustrated by the lower line on Fig. 1. This result and its physical meaning will be discussed further below. The curves for 1 < co consist of the sum of two exponentials and approach the equilibrium state more rapidly. The impulse results are shown in Fig. 2 for a = 0.3. Here the curves

IO 0.5

x -P

0.1 0 05

0.01

IO

20

2,0

FIG.

2. Response to i.v. pulse injection,

a = 0.3. (a) Compartment

1, (b) compart-

nent 2.

70

K.

B.

BISCHOFF

AND

R.

L.

DEDRICK

decrease sharply for short times, and then decrease more slowly, approaching a single exponential. This represents the typical case where the short time behavior is dominated by body redistribution and the long time behavior by elimination. For 3, -+ co, it can be shown that (17) yip = yzp + e-. Even though the long time behavior is dominated by elimination, the slope of the line is not the elimination rate constant. This point has recently been discussed at length by Wagner & Northam (1967) and by Riegelman et al. (1968a). Their arguments will not be repeated here, but it is noted that the dimensionless solutions give the same conclusions. At long times, the dominant term in equation (12) is the one containing r2. which is the smallest (negative) root,

The slope of a plot equation (1 l),

of concentration

vs. dimensional

time

is, from (19)

Slope = k,, = Ir,l ( K-:Fvi)

where k,, is the specific elimination rate constant as commonly used in one-compartment analyses. Thus, k,, is not equal to the physically defined specific elimination clearance in the two-compartment model unless /? -+ GO, in which case lrzl = 1. In general, r2 is a function of both c(and i, and when 2 is small, r2 -+ 1(1 +a), thus leading to very large differences. In fact, for A + 0, the rl term dominates, and the dimensional slope becomes k,, = !?
k ___.--

- = -k
v,

SI V;+lcI/,

(20)

Equation (20) is physically reasonable since A -+ 0 implies Q, -+ 0, isolation of the tissue compartment from the central compartment. Estimates of the errors involved in assuming k,, = k/(Vl +KV,) are provided in graphical form by Wagner & Northam (1967); further discussion on some practical aspects is given by Riegelman et al. (1968a). Another common procedure that is invalid when the two-compartment model is required is to extrapolate the straight line portion of the curve to r = 0 and use this intercept to find the volume of distribution. The above authors, as well as Riegelman et al. (1968b), have discussed this issue in some detail. From equation (18), the dimensional intercept of this type of extrapolation is : M M l+cc r,+A(l+a) cI -~___Intercept = (v,>i = v, + Key (21) [ f-2 - rl 1

TWO-COMPARTMENT

OPEN

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71

where (l~,)~ is the apparent volume of distribution from the intercept. Thus, (lag is different from (V,+KF/,) except as ;1 -+ co when the term within square brackets in equation (21) approaches unity. Again, for 1 -+ 0 the r1 term is dominant and (22) giving (23) Thus, (Vd)i gives the proper result only in the two extremes when the two exponential solution reduces to a single exponential. It will be shown below that A -+ co corresponds to taking the whole body as one compartment and, as just discussed, I --f 0 corresponds to the central compartment only being involved. Both such cases approach the one-compartment models for which the traditional method of extrapolation is satisfactory. For intermediate values of A, Wagner & Northam (1967) give the differences between (Vd)i and (Vi +KVJ. A table of rl and r2 as functions of CI and L is given in Appendix B for use with equations (19) and (21). An alternate way of determining the apparent volume of distribution was proposed by Wagner & Nelson (1964) in which the area under the pulse curve is used: (34) Their work was based on a one-compartment model. For the two-compartment model, and with normalized dimensionless concentrations.

Using equation (19) gives

and, comparing with equation (24)

Thus, again (V,), does not give the proper result for 0 < i. < co, although the deviation will be different than those from (Qi of equation (21). Riegelman et al. (19683) give some relevant numerical examples.

72

K.

B. BISCHOFF

AND

R. L.

DEDRICK

I.0 2 2

0.5

01

0.2

0.4

0.6

0.8

I.0

I2

I4

FIG. 3. Response to i.v. pulse injection, a = 0.3, short time behavior

IO r

20

FIG. 4. Response to i.v. pulse injection, a = 0.2, compartment

1.

TWO-COMPARTMENT

OPEN

MODEL

73

FIG.

5. Response to G.I. -% compartment 2.

pulse,

cz = 0.3, I = I .o. ___

compartment

1;

FIG. 6. Response to G.I. -- - - -, compartment 2.

pulse, LI = 0.3. 1 1 20. -,

compartment

1:

74

K.

B.

BISCHOFF

AND

R.

L.

DEDRICK

Figure 3 shows the short time behavior in more detail for large i., and It can be seen how the curves approach the single exponential as L --f YL, Figure 4 presents the solution for a value of CY 0.2. Comparison of Figs. 2 = and 4 shows that the two sets of curves are similar and that their behavior is not very sensitive to the volume ratio parameter, CX. Figures 5 and 6 introduce the parameter [. It is seen, for large [ values (e.g. i > lo), that there is little difference between the curves, except for the level. From equation (12) and a similar result for G.1. absorption, it can be shown that for long times, the ratio approaches:

bl,h
CY1P)i.v.

_
l+

1
r.Zli

(28a) (28b)

Thus, with this correction, it would often be acceptable to use the i.v. curves and ignore the G.I. absorption aspects. Somewhat similar behavior is evident in the work of Kruger-Thiemer (1966) for the one-compartment model which has been studied in detail for certain special cases by Wagner (1967).
5. Limiting Forms of Solutions

From inspection of the above graphs, it can be seen that the results approach various limiting forms for certain values of the parameters. Equations (16) and (17) imply that the solutions become equivalent to onecompartment results for the case where 1 + co. Physically, since A = Q,/k, this means that the flow interchange between the body compartments is much more rapid than the total elimination rate. In other words, elimination is the rate controlling step and internal differences in free concentrations are negligible. The term E-limited is used here to denote this eliminationlimited situation which is somewhat analogous to the flow limited assumption for local tissues. It is of interest to develop criteria for when a system is E-limited, which would also serve for selecting a one-compartment or twocompartment model. Formal expansion of the various solutions in (l/A) yields the desired results. From equation (13), the roots become

(2%

TWO-COMPARTMENT

OPEN

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75

Using these in the solution for an i.v. impulse, equation (12) leads to

l.Y,P)i.y.+cOw2 =i1 z(1 lexN +; [ l-+l+a)-2 I exp r -+ I -i(l+a)-l] [ -+e-, A-+00. exp{-

1- ++a)-2 (1+co2 -A-----

13
[ 1+ f(l+a)- i r) 0 (304 11

[I -i(r+a)-2]

(3Ob)
(30c)

Equation (30~) is the completely E-limited result, and equation (30b) is a first-order correction for the straight line portion. Likewise,

+e-,

A-+-co. for use of the one-compartment, 1 >>++zi-2. E-limited

(3lc) results is: (32)

Thus, the criterion

If equation (32) is satisfied, the single exponential equations (30~) and (31~) should be satisfactory. The equations can also be used to develop a relation for the beginning of the straight line portion of the curve. This is equivalent to determining when the magnitude of the rl exponential is much larger than the r2 exponential. From equation (12) this is: err > erir or erzr > t erlr where l is a number, say 100 or 1000. Equation
(r2 - rr)t > In l

(33) (33) can be modified to Wa)

76

K.

B.

BISCHOFF

AND

R.

L.

DEDRICK

which for large II and using equation (29) becomes,

Calculations with equation (34) and comparison with Figs 2, 3 and 4 show that a value of In 5 N 8 indicates the approximate beginning of the straight line portion of the curves. For values of c( N 0.2 to 0.3, equation (34b) gives a simple approximate criterion, /IT > 1.2. (34cJ

Another relation of interest indicates the difference between the two free concentrations in the straight line portion. For long times, the ratio of the result for compartment 2 to equation (12) is

Which for large 1 becomes,

[ 1
Equation to (30b). for large Similar (ylP)G,I, = (4 [I - +f

(Y2P)i.v. (Y1P)i.v. larger=

1 + 4l +cr> + * 0

(35b)

(35b) could also be derived by taking the ratio of equations (31b). Thus the deviation between the two compartment concentrations but finite I is roughly l/L. limiting results are obtained for the G.I. impulse results, (2 + ,_i)] exp { - [ 1 - k (1 +a)-] T>

c -y, -+ c-1 (e-r-e

1 -+ co

TWO-COMPARTMENT

OPEN

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77

and,

e-i

1(1+a)-i

(r-1

[ -1 +(l+a)- i-1

+ il(l+z)

-l+l(l+cr) (cc-1 1(1+a)2 ---C@ r c? i) + JL i-1 Other limiting (e-r-e-cz), A-+ ~0.

(374

(37b)

solutions for 1 -+ 0 and [ + co have been presented above.

6. Use of General Solutions

The most obvious application of the general formulas and graphs is that given V,, KV,, Q, and k, the proper dimensionless curve can be chosen for the c1= V,/KV, and A = QJk, ordinate and abscissa points read off for y and T, which when multiplied by the dimensional ratios give a set of predicted C(t) curves. Usually, however, ail of these physiological parameters are not readily available. Reasonable a priori values for V,, $3, and Q, can be estimated, but the metabolism and excretion rates represented by the elimination constant, k, must often be found from the in viva data that one is trying to predict. In other words, the physical parameters can be predicted, but the chemical factors cannot be, at least at the present time. Thus the general solutions can be used given a priori V,, Klr,, Q,, and the observed long time slope, kel. It was pointed out above that k,, is nof the same the model parameter, k/( V, + KV2), and that the proper k must be obtained from the measured k,,. Equation (19) shows how they are related, and if

78

I<.

B.

BISCHOFF

AND

R.

L.

DEDRICK

equation (13) for r2 is substituted, the solution for i, (or k, with Q1 ) becomes (38a)
= f ,~~j, + O (~),

where (38~) Thus, with equation (38) one can properly determine k from the experimentally measured slope, k,,. Another use of the general graphs is an aid to curve fitting. It is not felt that this is as meaningful as insisting that as much a priori information as possible be used, but sometimes it is the only recourse. Rough estimates of the values of the parameters may be found using a curve fitting procedure to determine the parameters so that the experimental curve matches the model curve. Since general dimensionless plots contain all possible curves that can be generated by the two-compartment model, one of them, when multiplied by the proper dimensional scale factors, should match the experimental curve. The scale factors, of course, contain the unknown parameters and since multiplying a curve by a constant changes its shape, such straightforward graphical matching procedures are very difficult. The use of log-log plots can avoid this difficulty. Since the logarithm of the product of two numbers is the sum of the logarithms of each of the numbers, on a log graph scale, multiplication by a factor is equivalent to adding the log of the factor. Thus, rather than stretching the curve as on an arithmetic scale, a constant distance is added, or the curve is just shifted parallel to the axis on a log plot. Thus, if the experimental dimensional curve is superimposed on the model dimensionless curves (by transparent graph paper), shifting the two until a model curve is found that matches the experimental one will provide the values of the scale factors by comparing the numbers on the axes. Only movements keeping the axes parallel to each other are allowed, with no relative rotation of the two graphs. Figure 7 is a log-log plot of Fig. 2 and can be used in this way. The curves for different values of the parameters have fairly distinct shapes, making it easier to select the proper model curve. Of course, as with many graphical procedures, the accuracy may not be satisfactory and better estimates might be found from nonlinear regression using computers to fit exponential functions. The rough estimates which can be readily obtained from the graphical procedure are useful as initial guesses for regression analyses.

o-01

01

I.0

I Cl

FIG. 7. Curve fitting plots, C = co. (a) a = 0.2, (b) n = 0.3, (c) a = 04

80

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DEDRICK

REFERENCES
BISCHOFF, K. B. & DEDRICK, R. L. (1968). J. Phurm. Sci. 57, 1346. DEDRICK, R. L. & BISCHOFF, K. B. (1968). Chem. Engng. Progr. Symp. Ser. No. 84,64, 32. DOMINGLJEZ (1935). Am. J. Physiol. 114, 204. DOST, F. D. (1953). Der Blutspiegel. Leipzig: Thieme. HIMMELBLAU, D. M. & BISCHOFF, K. B. (1968). Process Analysis and Simulation. New York: John Wiley. KAPLAN, W. (1962). Operational Methods for Linear Systems. Reading, Mass. : Addison Wesley. KRUEGER-THIEMER (1966). J. theor. Biol. 13, 212. MAPLESON, W. W. (1963). J. nppl. PhysioI. 18, 197. MORALES, M. F. & SMITH, R. E. (1948). Bull. math. Biophys. 10, 19 I. RIEGELMAN, S., Loo, J. C. K. & ROWLAND, M. (196%~). J. Pharm. Sci. 57, 117. RIEGELMAN, S., Loo, J. C. K. & ROWLAND, M. (19686). J. Pharm. Sci. 57, 128. RIGGS, D. S. (1963). Mathematical Approach to Physiological Problems. Baltimore: Williams and Wilkins. TEORELL, T. (1937). Archs int. Pharmacodyn. ThPr. 57, 205. WAGNER, J. G. (1967), J. Pharm. Sci. 56, 586. WAGNER, J. G. (1968). J. theor. Biol. 20, 173. WAGNER, J. G. & NELSON, E. (1964). J. Pharm. Sci. 53, 1392. WAGNER, J. G. & NORTHAM, J. I. (1967). J. Pharm. Sci. 56,529. WAGNER, J. G., NOVAK, E., LESLIE, L. G. & METZLER, C. M. (1968). ht. J. din. Pharmacol. 1, 261. WAGNER, J. G. & METZLER, C. M. (1969). J. Pharm. Sci. 58, 87. WIEGAND, R. G., BUDDENHAGEN, J. D. & ENDICO~, C. J. (1963). J. Pharm. Sci. 52,268. WILDE, D. J. & BEIGHTLER, C. S. (1967). Foundations of Optimization. Englewood Cliffs, N.J. : Prentice-Hall.

APPENDIX

Parameter Values Development of mathematical models to predict drug distribution in the body on the basis of physiological, anatomical and physicochemical data has been discussed previously (Bischoff & Dedrick, 1968; Dedrick & Bischoff, 1968). When the four-compartment model derived for barbiturates is reduced to the linear two-compartment model and balances are based on free concentrations, the physical meaning of VI and V, in equations (1) and (2) is:

y =fI3PB+ ~,)ff, ~T+m -ffJWIl+ Vd+(1 -fvT)VTI v, =fB(I/LB+~B)+fLTT/LT+BA(l-fAT)VAT

+W -fdV~,+ v,,)+(l -f~,>v,,l.
Equations (Al) and (A2) incorporate

(Al)
642)

the concepts of effective protein

TWO-COMPARTMENT

OPEN

MODEL

81

fractions, f, d iscussed in the above references, linear protein binding constant B, and lipid solubility constant, BA. Definition of compartment volumes, V, and their numerical values for a 70 kg man are given in Table Al. Then
V, 210*94(2.2+ 2.5) +0*88(6*2) + B[O*06(2*2+ 2.5) + O-12(6.2)] = 9.9 + 1.03B. k; 0*94(0~52+0~16)+0~91(39~2)+0~20(12-2) (.43)

+ B,(0*80)(12.2) + B[O-06(0.52 + 0.16) + 0*09(39-2)]

= 38.8+3.6B+9-8B,. (.44)
TABLE

Al

Physiological volumesfor a 70 kg man basedon anatomical breakdown7

Compartment Blood not in equilibrium with tissues Blood in equilibrium with viscera Blood in equilibrium with lean tissue Blood in equilibrium with adipose tissue Viscera tissue Lean tissue Adipose tissue t Values from Mapelson (1963). Symbol Volume, I

VB V"B VLB V*El VW VLT VAT

2-2 2.52 0.52 0.16 6.2 39.2

12.2

Therefore, with balances written in terms of free concentrations

9-9 + 1.03B = 3x8+3*6B+9*8BA

(K = I),
(A5)

Equation

(A5) can be used to determine various limiting

values of CI:

(a) For no binding or lipid solubility,

a = .E = 0.25. 38.8

B-.o

BA-0

(b) For large degree of binding and no lipid solubility,

a
B-rm

=-- t;6 = 0.29.

82

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BISCHOFF

AND

R.

L.

DEDRICK

Other values of B could be used, and u would fall between the above two numbers. Large lipid solubilities could cause CI < 0.25, but for many drugs this is not important. The flow limiting equations used here implicitly contain the assumption of infinite or zero membrane permeabilities depending on the possible distribution of the drug being throughout the tissues or just in extracellular fluid. Of course, empirical values of the volumes could be used for intermediate cases, but then the a priori prediction is lost. Thus, for the second extreme of only extracellular water, using interstitial fluid as - 20 to 30 (, of tissue mass, V;, r 0.25(6.2) = 1.6, VtT 2c 0.25(39+2) = 9.8. Calculations similar to those done above then yield

57+0*48B
a = 12.0+0.92B+9.76BA Then the same two limits give: (a) For no binding, u = 0.48.
B-+0 BA+O

(A(5)

(b) For large degree of binding, u = 0.52.

B+CC BA-+O

It is seen that usually 0.25 < a < 0.52 for most drugs of interest except those of high lipid solubility where CI < 0.25, and the computations discussed above have been done for only this range of values, although any value can be easily used in the computer program. The intercompartment transport parameter, Q,, is defined for the case being considered in terms of the physiological blood flow to the lean and adipose tissues, Q, corrected for binding: QI E QVB+B(l-~B)I (A7)

where Q II 1.5 l/min (Mapleson, 1963). Parameters for binding, metabolism and excretion must generally be determined individually, as these vary widely among drugs and even between individuals.

CONTROL

OF

DISPLAYS

91

the average, than those recorded for mammals and birds. The primates recorded also average higher than the other mammals. These apparent differences may be pure artefacts. Insectivores, rodents, carnivores and ungulates probably use relatively more olfactory and tactile signals, and a greater variety of such patterns, than do primates. Similarly, fish probably have more olfactory and tactile displays (which may be particularly difficult to observe) than do any birds or all or most of the mammals. It should also be mentioned that all the fish cited were observed in aquaria, in more or less severely restricted and abnormal conditions, while most of the birds and mammals were studied at least partly in the wild (although not always at all times of the year or in all the environments inhabited by the species). Thus, some of the figures cited are probably more strongly underestimated than others. The ones most likely to have been most underestimated are marked by daggers. As a general conclusion, it may be said that the picture conveyed by the table as a whole is incomplete, even a distortion of reality. However the summaries of individual species repertories are probably all distorted in some of the same ways, and they are as nearly strictly comparable as is possible in the present state of our knowledge. Crude and approximate as these figures may be, they clearly indicate that the number of major displays in the repertories of many adult vertebrates varies only within certain, and comparatively narrow, limits. No species has been found to have only two or three displays of this type. Nor has any species been found to have as many as 40 or 45. Probably, the great majority have between 15 and 35. This range may appear to be substantial, but it is a very great deal less than would be theoretically conceivable. Other groups of animals may be less conformist, or conform to other standards. J have not attempted to list numbers of major displays in invertebrates; partly because of general unfamiliarity with the literature and partly because none of the few works on invertebrates which has come to my attention has dealt with the whole of the social behavior of an undomesticated species. Dr A. S. Rand has suggested to me that most lizards and frogs may have significantly fewer displays, on the average, than even the most poorly provided fish or mammal cited above. There would appear to be at least some exceptions (see, for instance, the chameleons described by Kiistle, 1967, and possibly the pipid frogs described by Rabb & Rabb, 1963), but the suggestion may still be valid for the majority of species of both groups. If so, their poverty in displays might be due to the fact that they are comparatively exl.remely vulnerable to predators. They tend to be smaller than many birds and