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COMPARTMENT MODELS OF

DRUG DISTRIBUTION
Pharmacokinetic Modeling
approaches
There are three approaches that have been suggested for
pharmacokinetic modeling,

Compartmental model
Physiological model
Model independent approach
Compartmental model

The first is an empirical approach, which is based on a


simple compartmental model.
These compartments have no strict physiological or
anatomic basis.
The compartment can represent a body volume, or just
as easily it could represent a chemical state, for example a
metabolite of the drug.
Usually this approach uses one or two compartments.
Despite its simplistic nature, many useful quantities can
be derived using this approach and by comparing
predicted values with actual data.
Physiological model

The physiological model identifies the compartments with


actual body spaces.
The model is a great deal more complex than the
compartmental models.
Actual transfer and flow rates are employed together with
experimentally measured blood/tissue concentration
ratios.
This model can be used for predictions, and is more
adaptable to clinical therapy and to changing situations
such as alterations of flow rates due to conditions such as
swelling, or fever.
Model independent approach
The is the most recent, and is purely mathematical.
It avoids recourse to kinetic parameters which may not
be valid, and is a lot less complex.
It is good for absorption and elimination rates, and
clearances, but gives no specific information about how
the drug is distributed.
Compartmental model
The compartment concept is utilized in pharmacokinetics
when it is necessary to describe the plasma concentration
versus time data adequately and accurately
To obtain accurate estimates of selected fundamental
pharmacokinetics parameters such as the apparent volume
of drug distribution, the elimination half life and the
elimination rate constant of a drug.
Constitute the basis for the calculation of the dosage
regimen (dose and dosing interval) that will provide the
desired plasma concentration and duration of action for an
administered drug
Compartmental model
Compartmental analysis is the traditional and most
commonly used approach to pharmacokinetic
characterization of a drug.

In this, body is considered to be composed of several


compartments that communicate reversibly with each
other.

As infinite number of compartments can exist in body


(each organ, tissue or body fluid can a form a
compartment), tissues having approximately similar drug
distribution are pooled to form a kinetically
homogeneous hypothetical compartment.
The selection of a compartment model solely depends upon the distribution
characteristics of a drug following its administration
The equation required to characterize the plasma concentration versus time
data, however, depends upon the compartment model chosen and the route
of drug administration.
The selected model should be such that it will permit accurate predictions in
clinical situations.
Generally, the slower the drug distribution in the body, regardless of the
route of administration, the greater the number of compartments required
to characterize the plasma concentration versus time data, the more complex
is the nature of the equatio
Slow distribution suggests that the distribution equilibrium is attained slowly
and at a finite time (from several minutes to a few hours, depending upon the
nature of the administered drug).
Furthermore, it suggests that the vasculature,tissues and organs are not
behaving in a similar fashion toward this drug and, therefore, it may be
considered that the body to comprise two compartments or, if necessary,
more than two compartments.
Highly perfused systems: liver, the kidney and the blood, may
be pooled together in one compartment (i.e. the central
compartment: compartment 1)
Systems that are not highly perfused; bones, cartilage, fatty
tissue and many others, can also be pooled together and
placed in another compartment (i.e. the tissue or peripheral
compartment: compartment 2).
In this type of model, the rates of drug transfer from
compartment 1 to compartment 2 and back to compartment
1 will become equal at a time greater than zero (from several
minutes to a few hours).
Such compartments are, thus, only mathematical entities
and have no physiological or anatomical meaning.

Generally, model consisting of one, two or at the most


three compartments arranged parallel to each other are
used to describe kinetics of most drugs.

These compartments are called open models because


there is no restriction to the movement of drugs between
compartments as drugs freely move from one
compartment to the other.
It is also assumed that the rate of drug transfer between
compartments and the rate of drug elimination from
compartments follow first-order or linear kinetics.

Compartment characteristics of a drug are best


understood by giving it as intravenous bolus and observing
the manner in which the plasma concentration declines
with time

The number of exponents required to describe such a


plasma level-time profile determines the number of
compartments in which a drug will distribute.
Rate of Transfer of drug between
compartments
Rates of reaction
The transfer of drug between the compartments is
represented by rate constants
The rate of a reaction or process is defined as the velocity
at which it proceeds and can be described as either zero-
order or first-order.
Zero-order reaction
Consider the rate of elimination of drug A from the body. If
the amount of the drug, A, is decreasing at a constant rate,
then the rate of elimination of A can be described as:

where k* the zero-order rate constant.


The reaction proceeds at a constant rate and is
independent of the concentration of A present in the
body.
An example is the elimination of alcohol.

Drugs that show this type of elimination will show


accumulation of plasma levels of the drug and hence
nonlinear pharmacokinetics.
First-order reaction
If the amount of drug A is decreasing at a rate
that is proportional to A, the amount of drug A
remaining in the body, then the rate of
elimination of drug A can be described as:

where k the first-order rate constant


The reaction proceeds at a rate that is dependent on
the concentration of A present in the body.

It is assumed that the processes of ADME follow


first-order reactions and most drugs are eliminated in
this manner.

Most drugs used in clinical practice at therapeutic


dosages will show first-order rate processes.

However, there are notable exceptions, for example


phenytoin and high-dose salicylates.
For drugs that show a first-order elimination process,
as the amount of drug administered increases, the
body is able to eliminate the drug accordingly and
accumulation will not occur.

If you double the dose you will double the plasma


concentration.

However, if you continue to increase the amount of


drug administered then all drugs will change from
showing a first-order process to a zero-order process,
for example in an overdose situation.
It is important to note that this does not imply that the
drug concentration in plasma (Cp) is equal to the drug
concentration in the tissues.

However, changes in the plasma concentration


quantitatively reflect changes in the tissues.

When plotted on a log Cp vs time graph they show a


linear relation; this represents a one-compartment
model.
Conc. vs. time plots
Types of Kinetics Commonly Seen
First Order Kinetics
Zero Order Kinetics
Rate = k C
C = Co e-kt
Rate = k
Rate of elimination
C = Co - kt proportional to
Constant rate of plasma
elimination regardless concentration.
of [D]plasma Constant fraction of
drug eliminated per
C vs. t graph is LINEAR unit time.
C vs. t graph is NOT
linear, decaying
exponential. Log C vs.
t graph is linear.
First-Order Kinetics
Comparison

Zero Order Elimination First Order Elimination


[drug] decreases linearly [drug] decreases
with time exponentially w/ time
Rate of elimination is Rate of elimination is
constant proportional to [drug]
Rate of elimination is Plot of log [drug] or
independent of [drug] ln[drug] vs. time are
No true t 1/2 linear
t 1/2 is constant regardless
of [drug]
One-Compartment Open Model
One-compartment open model is the simplest model,
which considers the whole body as a single, kinetically
homogeneous unit.

In this model, the final distribution equilibrium between


the drug in plasma and other body fluids is attained rapidly
and maintained at all times.

Any change in the plasma levels of drug reflects


proportional changes in tissue drug concentrations.
The one-compartment open model applies to only those
drugs, which distribute rapidly throughout the body.

The model is generally used to describe plasma levels


following administration of a single dose of a drug, and can
be observed following either intravenous bolus or
extravascular administration of drugs.
Intravenous bolus administration: When a drug that
distributes instantaneously in body is given as rapid IV
bolus, the entire dose of drug enters the body and is
distributed immediately via circulation to all tissues.
In such a situation, the drug concentration-time curve will
be obtained as a straight line on semi-logarithmic paper
showing monophasic exponential decline.
In this model, the decline in plasma drug concentration
occurs only due to elimination of drug from the body,
therefore, the phase is called the elimination phase.
The distribution phase is normally neglected in
calculations because distribution is so rapid that it cannot
be shown on graph.
The extrapolated zero-time intercept of linear elimination
phase gives the coefficient B, and the elimination rate
constant is given by .

The value of B is an estimate of zero-time concentration


of drug in plasma (C0or Cp).

Extravascular administration: When a drug is


administered by extravascular route (e.g., oral, IM, SC,
etc.), absorption is a pre-requisite for its action.
If it is distributed according to one compartment open
model, the rate of change in drug concentration in the
central compartment is described by 2 exponents - an
absorption exponent and an elimination exponent.
Intravenous bolus administration, one-compartment model
Intravenous bolus administration, one-compartment model

The plotted curve is a straight


line, which clearly indicates the
presence of a single
pharmacokinetic phase (namely,
the elimination phase.)
Since the drug is administered
intravenously, there is no
absorption phase.
The straight line also suggests
that distribution is instantaneous;
thus the drug is rapidly
distributed in the body.
These data can be accurately and
adequately described by
employing the following mono-
exponential equation
This approach models the entire body as a single
compartment into which drug is added by a rapid single
dose, or bolus.
It is assumed that the drug concentration is uniform in
the body compartment at all times and is eliminated by a
first order process that is described by a first order rate
constant kel.
The one compartment model fails to describe the actual
drug disposition
for example, a particular organ has a small, but strong
affinity for a drug, which does not affect the overall
plasma concentration, but which leads to toxicity on
repeated doses.
If this area is the site of drug action, the effect could
continue after blood levels had subsided.
Extravascular administration: one-compartment model
Two phases in the profile: absorption
and elimination.
The profile clearly indicates the
presence of only one phase in the
post-absorption period.
Since distribution is the sole property
that determines the chosen
compartment model and, since the
profile contains only one phase in the
post-absorption period,
These data can be described accurately
and adequately by employing a one-
compartment model.
However, a biexponential equation
would be needed to characterize the
concentration versus time data
accurately.
Two-Compartment Open Model
Two-compartment open model assumes that body is
composed of two compartments
Central compartment
Peripheral compartment.

The central compartment (compartment 1) consists of


blood and highly perfused organs like liver, kidneys, lungs,
heart, brain, etc;

The less perfused tissues like skin, muscles, bone,


cartilage, etc. make the peripheral compartment
(compartment 2).
The drug is directly administered (IV route) or absorbed
(extravascular route) into the central compartment and
various organs in it rapidly equilibrate with it.

Elimination of drug occurs from central compartment


since main organs involved in drug elimination (e.g. liver
and kidneys) are located in it.

The distribution of drugs to peripheral compartment is


through blood (central compartment) and occurs slowly.
It is assumed that drug transfer from central compartment
to peripheral compartment, and back from peripheral
compartment to central compartment occurs by first-order
process and is defined by rate constants denoted by letter
k.

The subscript indicates the direction of drug movement


e.g., k12 refers to drug movement from compartment 1
(central compartment) to compartment 2 (peripheral
compartment), and reverse for k21 (Figure 5.2).

The two compartment open model adequately describes


the disposition kinetics of most therapeutic agents in
humans and animals.
Intravenous bolus administration:
After the intravenous bolus administration of a drug that
follows two-compartment kinetics, the decline in plasma
concentration is biexponential.

When plasma drug concentration-time curve is plotted on


a semi-logarithmic paper, the plasma concentration
declines rapidly in first phase followed by a slow terminal
decline.

The initial steep decline in drug concentration is


attributed mainly to distribution of drug from the central
compartment to the peripheral compartment, and
terminal shallow decline is mainly due to elimination of
drug from the central compartment.
The linear terminal portion of curve is called the
elimination phase.

The extrapolated zero-time intercept of linear distribution


phase (residual line) is denoted by letter A, and the
elimination phase by letter B
The sum of A and B coefficients gives the initial
concentration of drug in the plasma (C0 or Cp).

For two compartment model, a is the rate constant for


distribution, and is the rate constant for elimination; they
are expressed in units of reciprocal time (min1).

is used for rate constant for elimination from the entire


body, whereas Kel is used for rate constant for elimination
of drug from the central compartment.

In drug disposition studies, the coefficients (A and B) and


rate constants ( and ) are calculated from the
experimental data by least square regression analysis.
Two-Compartment Open Model, Intravenous administration
Two-Compartment Open Model, Intravenous administration

The first phase (curvilinear portion)


represents drug distribution in the
body; and only after a finite time
(indicated by a discontinuous
perpendicular line) do we see a straight
line.
The time at which the concentration
versus time plot begins to become a
straight line represents the occurrence
of distribution equilibrium.
This suggests that drug is being
distributed slowly and requires a two-
compartment model for accurate
characterization.
The equation employed to characterize
these plasma concentration versus time
data will be biexponential (contain two
exponential terms):
A and alpha are parameters associated with drug distribution and B and beta are
parameters associated with drug post-distribution phase.
Two compartment model: Extravascular administration:
For a drug that enters the body by an extravascular route
(e.g., oral, IM, SC, etc.) and is distributed according to
two compartment model, the rate of change in drug
concentration in plasma is described by 3 exponents
1. Ka an absorption exponent,
2. a distribution exponent and
3. an elimination exponent.
Extravascular route of drug administration, two-compartment mod

The presence of three phases in the


plasma concentration versus time
data for a drug administered by an
extravascular route.
Three phases include absorption,
distribution and post-distribution
The plasma concentration versus time
profile, in the post-absorption period
looks identical to that for an
intravenous bolus two-compartment
model
These data, therefore, can be
described accurately by employing
a two-compartment model and the
equation will contain three
exponential terms (one for each
phase: absorption, distribution, and
postdistribution.)
.
Three-Compartment Open Model

The pharmacokinetic behaviour of some drugs, which have


a high affinity for a particular tissue or undergo
redistribution, is best interpreted according to a three
compartment open model.

In this compartmental model, body is conceived as


consisting of three compartments one central and two
peripheral compartments.
The central compartment (Compartment 1) comprises of plasma
and highly perfused organs,
Compartments 2 comprise of moderately perfused tissues e.g.,
skin and muscles
Compartments 3 comprise poorly perfused tissues - e.g., bone,
teeth, ligaments, hair, and fat

If a drug is administered in body by intravenous bolus injection,


it is first distributed immediately into the highly perfused tissues
(compartment 1), then slowly into the moderately perfused
tissues (compartment 2) and thereafter very slowly to the poorly
perfused tissues (compartment 3).

If plasma level-time profile is plotted on semi-logarithmic graph,


it gives a triexponential appearance.
(a) Plasma concentration versus time profile of a drug showing multicompartment
model. (b) Time profile of a multicompartment model showing
log Cp versus time.
II.NON-COMPARTMENT MODELS/NON-
COMPARTMENT ANALYSIS

Non-compartment analysis is another approach to study the


time course of drugs in body.
It does not require the assumption of specific compartment
model.
It considers the time course of drug concentration in plasma
as a statistical distribution curve and derives
pharmacokinetic parameters by simple algebraic
equations.
The disadvantage of this method is that it often deals with
averages and provides limited information regarding plasma
drug concentration-time profile.
II.NON-COMPARTMENT MODELS/NON- COMPARTMENT ANALYSIS

The noncompartmental approach for data analysis does not require any specific
compartmental model for the system (body) and can be applied to virtually any
pharmacokinetic data.
Various noncompartmental approaches: statistical moment analysis, system analysis,
or the noncompartmental recirculatory model.
The main purpose of the noncompartmental approach is to estimate various
pharmacokinetic parameters, such as systemic clearance, volume of distribution at
steady state, mean residence time, and bioavailability without assuming or
understanding any structural or mechanistic properties of the pharmacokinetic
behavior of a drug in the body.
In addition, many noncompartmental methods allow the estimation of those
pharmacokinetic parameters from drug concentration profiles without the complicated,
and often subjective, nonlinear regression processes required for the compartmental
models.
Owing to this versatility and ruggedness, the noncompartmental approach is a primary
pharmacokinetic data analysis method for the pharmaceutical industry
Moment analysis, the most commonly used noncompartmental method,
III. PHYSIOLOGICAL MODELS
Physiological models (perfusion rate-limited models)
technique is a newer approach devised to study the time
course of drugs in body.

The basis of this method is that each major organ system,


plus any specialised target site, represents a physiological
compartment.

Each separate compartment has its own blood flow, tissue


volume, uptake process, affinity for the compound (i.e.,
partition coefficient) and elimination process.
Thus, the kinetics of the drug is described by a series of flow-
related equations, which can be solved following the
incorporation of known physiological values (e.g., organ or
tissue volume, and perfusion rate) and experimental
estimates (e.g. tissue to plasma partition coefficients)

The physiological models have some advantages as they are


drawn on the basis of known anatomical and physiological
data and they present a more realistic picture of drug
disposition in various organs and tissues.

The physiological models also allow an assessment of the


impact of altered physiology (e.g. ageing) or pathology on the
drug disposition.
More importantly, species differences can be predicted
based on known perfusion rates.

The only disadvantage of physiological models is


obtaining experimental data, which is very exhaustive.
A physiological model.
Possibly the simplest application of multi-compartment
model is in the single-cell concentration monitoring (see
the figure above).
If the volume of a cell is V, the mass of solute is q, the
input is u(t) and the secretion of the solution is
proportional to the density of it within the cell, then the
concentration of the solution C within the cell over time
is given by
As the number of compartments increases, the model
can be very complex and the solutions usually beyond
ordinary calculation. Below shows a three-cell model
with interlinks among each other.
The formula for n-cell multi-compartment models
become:
Model topologies
As the number of compartments increase, it is challenging
both to find the algebraic and numerical solutions of the
model.

However, there are special cases of models, which rarely


exist in nature, when the topologies exhibit certain
regularities that the solutions become easier to find.

The model can be classified according to the


interconnection of cells and input/output characteristics:
Closed model: No sinks or source, lit.
Open model: There are sinks or/and sources among cells.
Catenary model: All compartments are arranged in a
chain, with each pool connecting only to its neighbors.
This model has two or more cells.
Cyclic model: It's a special case of the catenary model,
with three or more cells, in which the first and last cell are
connected
Mammillary model: Consists of a central compartment
with peripheral compartments connecting to it. There are
no interconnections among other compartments.
Reducible model: It's a set of unconnected models.
Pharmacokinetic parameters
Elimination rate constant
Consider a single IV bolus injection of drug X.
As time proceeds, the amount of drug in the body is
eliminated.
Thus the rate of elimination can be described (assuming
first-order elimination) as:

Hence
X= X0 exp(kt)
where X amount of drug X, X0 dose and k first-order
elimination rate constant.
Volume of distribution
The volume of distribution (Vd) has no direct
physiological meaning; it is not a real volume and is
usually referred to as the apparent volume of
distribution.
It is defined as that volume of plasma in which the
total amount of drug in the body would be required to
be dissolved in order to reflect the drug concentration
attained in plasma.

It is important to realise that the concentration of the


drug (Cp) in plasma is not necessarily the same in the
liver, kidneys or other tissues.
Then
Cp (plasma) =Vd X (tissues)
where Vd is the constant of proportionality and is
referred to as the volume of distribution, which thus
relates the total amount of drug in the body at any
time to the corresponding plasma concentration. Thus
Half-life
The time required to reduce the plasma
concentration to one half its initial value is
defined as the half-life (t1/2).
Consider
ln Cpt = ln Cp0 kt
Let Cp0 decay to Cp0/2 and solve for t=t1/2
This parameter is very useful for estimating how long
it will take for levels to be reduced by half the
original concentration.

It can be used to estimate for how long a drug should


be stopped if a patient has toxic drug levels, assuming
the drug shows linear one-compartment
pharmacokinetics.
Clearance
Drug clearance (CL) is defined as the volume of
plasma in the vascular compartment cleared of drug
per unit time by the processes of metabolism and
excretion.
Clearance for a drug is constant if the drug is
eliminated by first-order kinetics.
Drug can be cleared by renal excretion or by
metabolism or both. With respect to the kidney and
liver, etc., clearances are additive, that is:
CLtotal =CLrenal + CLnonrenal
Mathematically, clearance is the product of the first-
order elimination rate constant (k) and the apparent
volume of distribution (Vd).

Hence the clearance is the elimination rate constant


i.e. the fractional rate of drug loss from the volume
of distribution.
Clearance is related to half-life by
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