MULTICOMPARTMENT MODELS

(Delayed Distribution Models)

One-compartment model adequately describes pharmacokinetics of many drugs.
Instantaneous distribution equilibrium is assumed in such cases and decline in the
amount of drug in the body with time is expressed by an equation with a
monoexponential term (i.e. elimination). However, instantaneous distribution is not
truly possible for an even larger number of drugs and drug disposition is not
monoexponential but bi- or multi-exponential. This is because the body is
composed of a heterogeneous group of tissues each with different degree of blood
flow and affinity for drug and therefore different rates of equilibration. Ideally, a
true pharmacokinetic model should be the one with a rate constant for
each tissue undergoing equilibrium, which is difficult mathematically.
Multicompartment models are thus based on following assumptions –

1. Blood/plasma and the highly perfused tissues such as tissues such as brain, heart,
lung, liver and kidneys constitute the central compartment.

2. Other tissues with similar distribution characteristics are pooled together to

constitute peripheral compartments tissues on the basis of similarity in their
distribution characteristics.

3. Intravenously administered medications are introduced directly into the central

compartment.

4. Irreversible drug elimination, either by hepatic biotransformation or renal

excretion, takes place only from the central compartment.

5. Reversible distribution occurs between central and peripheral compartments,

with a finite time required for distribution equilibrium to be attained.

6. After drug equilibration between drug and the peripheral compartments,

elimination of drug follows first-order kinetics.

7. All rate processes involving passage of drug in and out of individual

compartment are first-order processes and plasma level-time curve is best
described by sum of series of exponential terms each corresponding to first-order
rate processes associated with a given compartment.

8. The peripheral compartment is usually inaccessible to direct measurement and is

not a site of drug elimination or clearance
Multicompartment characteristics of a drug are best understood by giving it as i.v.
bolus and observing the manner in which the plasma concentration declines with
time. The number of exponentials required to describe such a plasma level-time
profile determines the number of kinetically homogeneous compartments into
which a drug will distribute.

TWO-COMPARTMENT OPEN MODEL

The commonest of all multicompartment models is a two-compartment model. In
such a model, the body tissues are broadly classified into 2 categories –

1. Central Compartment or Compartment 1 comprising of blood and highly

perfused tissues like liver, lungs, kidneys, etc. that equilibrate with the drug
rapidly. Elimination usually occurs from this compartment.

2. Peripheral or Tissue Compartment or Compartment 2 comprising of

poorly perfused and slow equilibrating tissues such as muscles, skin, adipose, etc.
and considered as a hybrid of several functional physiologic units.

Classification of a particular tissue, for example brain, into central or peripheral

compartment depends upon the physicochemical properties of the drug. A highly
lipophilic drug can cross the BBB and brain would then be included in the central
compartment. In contrast, a polar drug cannot penetrate the BBB and brain in this
case will be a part of peripheral compartment despite the fact that it is a highly
perfused organ.

The plasma concentration for a drug that follows a two-compartment model

declines biexponentially as the sum of two first-order processes – distribution and
elimination.

Depending upon the compartment from which the drug is eliminated, the two-
compartment model can be categorized into 3 types:

1. Two-compartment model with elimination from central compartment.

2. Two-compartment model with elimination from peripheral compartment.

3. Two-compartment model with elimination from both the compartments.

In the absence of information, elimination is assumed to occur exclusively from

central compartment.

Two-Compartment Open Model

Intravenous Bolus Administration
The model can be depicted as shown below with elimination from the central
compartment.

After the i.v. bolus of a drug that follows two-compartment kinetics, the decline in
plasma concentration is biexponential indicating the presence of two disposition
processes viz. distribution and elimination. These two processes are not evident
to the eyes in a regular arithmetic plot but when a semilog plot of C versus t is
made, they can be identified (Fig. 9.12). Initially, the concentration of drug in the
central compartment declines rapidly; this is due to the distribution of drug from
the central compartment to the peripheral compartment. The phase during which
this occurs is therefore called as the distributive phase. After sometime,
a pseudo-distribution equilibrium is achieved between the two compartments
following which the subsequent loss of drug from the central compartment is slow
and mainly due to elimination. This second, slower rate process is called as
the post-distributive or elimination phase. In contrast to the central
compartment, the drug concentration in the peripheral compartment first increases
and reaches a maximum. This corresponds with the distribution phase. Following
peak, the drug concentration declines which corresponds to the post-distributive
phase (Fig.9.12).
Fig. 9.12. Changes in drug concentration in the central (plasma) and the
peripheral compartment after i.v. bolus of a drug that fits two-compartment
model.

Let K12 and K21 be the first-order distribution rate constants depicting drug transfer
between the central and the peripheral compartments and let subscript c and p
define central and peripheral compartment respectively. The rate of change in drug
concentration in the central compartment is given by:

Extending the relationship X = VdC to the above equation, we have

where Xc and Xp are the amounts of drug in the central and peripheral
compartments respectively and Vc and Vp are the apparent volumes of the central
and the peripheral compartment respectively. The rate of change in drug
concentration in the peripheral compartment is given by:
Integration of equations 9.85 and 9.87 yields equations that describe the
concentration of drug in the central and peripheral compartments at any given time
t:

where Xo = i.v. bolus dose, α and β are hybrid first-order constants for the
rapid distribution phase and the slow elimination phase respectively which depend
entirely upon the first-order constants K12, K21 and KE.

The constants K12 and K21 that depict reversible transfer of drug between
compartments are called as microconstants or transfer constants. The
mathematical relationships between hybrid and microconstants are given as:

α + β = K12 + K21 + KE (9.90)

αβ = K21KE (9.91)

Equation 9.88 can be written in simplified form as:

Cc = Ae –αα + Be βt (9.92)

Cc = Distribution exponent Elimination exponent

where A and B are also hybrid constants for the two exponents and can be resolved
graphically by the method of residuals.
where Co = plasma drug concentration immediately after i.v. injection.

Method of Residuals: The biexponential disposition curve obtained after i.v.

bolus of a drug that fits two compartment model can be resolved into its individual
exponents by the method of residuals. Rewriting the equation 9.92:

Cc = Ae -αα + Be -βt (9.92)

As apparent from the biexponential curve given in Fig. 9.12., the initial decline due
to distribution is more rapid than the terminal decline due to elimination i.e. the
rate constant α >> ß and hence the term e–αt approaches zero much faster than does
e–βt. Thus, equation 9.92 reduces to:

In log form, the equation

where C = back extrapolated plasma concentration values. A semilog plot of C

versus t yields the terminal linear phase of the curve having slope –β/2.303 and
when back extrapolated to time zero, yields y-intercept log B (Fig. 9.13.).The t ½ for
the elimination phase can be obtained from equation t½ = 0.693/β.

Subtraction of extrapolated plasma concentration values of the elimination phase

(equation 9.95) from the corresponding true plasma concentration values (equation
9.92) yields a series of residual concentration values Cr.
In log form, the equation becomes:

A semilog plot of Cr versus t yields a straight line with slope –α/2.303 and Y-
intercept log A (Fig. 9.13).

Fig. 9.13. Resolution of biexponential plasma concentration-time curve by the

method of residuals for a drug that follows two-compartment kinetics on i.v. bolus
administration.

Assessment of Pharmacokinetic Parameters: All the parameters of equation

9.92 can be resolved by the method of residuals as described above. Other
parameters of the model viz. K 12, K21, KE, etc. can now be derived by proper
substitution of these values.

C0 = A + B (9.99)
It must be noted that for two-compartment model, K E is the rate constant for
elimination of drug from the central compartment and β is the rate constant for
elimination from the entire body. Overall elimination t½ should therefore be
calculated from β.

Area under the plasma concentration-time curve can be obtained by the following
equation:

The apparent volume of central compartment Vc is given as:

Apparent volume of peripheral compartment can be obtained from equation:

The apparent volume of distribution at steady-state or equilibrium can now be

defined as:
It is also given as:

Total systemic clearance is given as:

The pharmacokinetic parameters can also be calculated by using urinary excretion

data:

An equation identical to equation 9.92 can be derived for rate of excretion of

unchanged drug in urine:

The above equation can be resolved into individual exponents by the method of
residuals as described for plasma concentration-time data.

Renal clearance is given as:

ClR Ke Vc (9.111)

Two-Compartment Open Model

Intravenous Infusion
The model can be depicted as shown below with elimination from the central
compartment.
The plasma or central compartment concentration of a drug that fits two-
compartment model when administered as constant rate (zero-order) i.v. infusion,
is given by equation:

At steady-state (i.e. at time infinity), the second and the third term in the bracket
becomes zero and the equation reduces to:

Now VcKE = Vdß. Substituting this in equation 9.113, we get:

The loading dose Xo,L to obtain Css immediately at the start of infusion can be
calculated from equation:

Two-Compartment Open Model

Extravascular Administration – First-Order Absorption
The model can be depicted as follows:

For a drug that enters the body by a first-order absorption process and distributed
according to two-compartment model, the rate of change in drug concentration in
the central compartment is described by 3 exponents —an absorption exponent,
and the two usual exponents that describe drug disposition.

The plasma concentration at any time t is given by equation:

C = Absorption exponent + Distribution exponent + Elimination exponent

where Ka, α and β have usual meanings. L, M and N are coefficients.

The 3 exponents can be resolved by stepwise application of method of residuals

assuming Ka > α > β as shown in Fig. 9.14. The various pharmacokinetic
parameters can then be estimated.
Fig. 9.14. Semilog plot of C versus t of a drug with two-compartment
characteristics when administered extravascularly. The various exponents have
been resolved by the method of residuals.

Besides the method of residuals, K a can also be estimated by Loo-Riegelman

method for a drug that follows two-compartment characteristics. This method is
in contrast to the Wagner-Nelson method for determination of K a of a drug with
one-compartment characteristics. The Loo-Riegelman method requires plasma
drug concentration-time data both after oral and i.v. administration of the drug to
the same subject at different times in order to obtain all the necessary kinetic
constants. Despite its complexity, the method can be applied to drugs that
distribute in any number of compartments.