TWO COMPARTMENT MODEL-

AN APPROACH FOR
PHARMACOKINETIC
DETERMINATIONS
 CONTENTS
• INTRODUCTION
• COMPARTMENT MODELS
• TWO COMPARTMENT MODEL(I.V BOLUS)
• METHOD OF RESIDUAL
• PARAMETERS OF TWO COMPARTMENT
• INTRAVENOUS INFUSION
• CLINICAL APPLICATIONS

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 INTRODUCTION
PHARMACOKINETICS:
• pharmacon: drug
• kinesis-motion/change of rate
Pharmacokinetics is the study of kinetics of absorption,
distribution, metabolism and excretion(ADME) of drugs
and their corresponding pharmacologic, therapeutic or
toxic responses in man and animals.

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 COMPARTMENT MODELS

Compartment models are classical pharmacokinetic models

that simulate the kinetic processes of drug absorption,
distribution and elimination with little physiologic detail.

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 COMPARTMENT MODEL
• A physiological system is described by decomposition into
number of interacting substances called compartments.
• Mass of well mixed, homogenous material.
• Behaves uniformly.
• Exchange material.

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 OPEN AND CLOSE MODEL
• OPEN MODEL:
Administered drug dose is eliminated from the body
by an excretory mechanism.

• CLOSED MODEL:
The drug dose is not eliminated from the body.

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 TWO COMPARTMENT MODEL
• Many drugs given in single IV bolus dose demonstrate a
plasma level time curve that does not decline as single
exponential process.
• In two compartment model, the plasma drug conc.
declines biexponentially as the sum of two first order
process, i.e distribution and elimination
• Does not equilibrate throughout the body

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• Drug distributes in 2 compartments

i.e. central compartment & tissue/ peripheral

compartment.

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 CENTRAL COMPARTMENT

• Represents the blood, extracellular fluid and highly

perfused tissues
• Drug distributes rapidly and uniformly

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 TISSUE OR PERIPHERAL COMPARTMENT

• Contains tissues in which drug equilibrates more slowly

• Drug transfer b/w the two compartments is assumed to

take place by first order processes

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 GENERAL GROUPING OF TISSUES
ACCORDING TO BLOOD SUPPLY
BLOOD SUPPLY TISSUE GROUP
• Highly • Heart, brain, hepatic portal
perfused vein, kidney and endocrine
glands, skin and muscles

• Slowly • Adipose tissue and marrow

perfused • Bone, ligaments, tendons,
cartilage, teeth and hair

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 MODELS OF TWO COMPARTMENT SYSYTEM

• They differ in whether the drug elimination occurs

from:
• the central compartment (Model A)
• the peripheral compartment (Model B)
• or both (Model C)

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 Cont….

• MODEL A:
Major sites of drug elimination occurs in organs such as
kidney and liver (highly perfused with blood).

• MODEL B:
Drug is assumed to follow the first order kinetics

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 RATE CONSTANTS

• Rate constants k12 and k21 represents the first order

rate transfer constants for the movement of drug from
compartment 1 to compartment 2 i.e. k12
• And from compartment 2 to 1 i.e. k21

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 CURVE OF THE TWO
COMPARTMENT MODEL
• Blood sampling

• Analyzed for drug content

• Distributive phase: drug is diffused into peripheral
compartment till equilibrium is attained
• Elimination phase

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 BASIC ASSUMPTIONS
• t=0
• After an I.V dose drug levels will first increase, reach
maximum and then decline

• tmax

• Distribution equilibrium

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 BIPHASIC EXPONENTIAL EQUATION

• Values of microconstants cannot be determined by direct

method, graphical method is used
a+b=k12+k21+k
Biphasic equation:
Cp=Ae-ᵃᵗ+Be-ᵇᵗ
A=D◦(a-k21)/Vp(a-b) : B=D◦(k21-b)/Vp(a-b)

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 METHOD OF RESIDUAL

• Useful procedure for fitting a curve to the experimental data

of a drug when drug does not clearly follow one compartment
model
• I.V administration of drug
• Blood sampling

• Assay
• Data is obtained and plotted on semi-log graph paper, curve
line is obtained

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 Continued….

• Curve line relationship b/w the log of the plasma conc. and
the time indicates that the drug is distributed in more than
one compartments
• So from data biexponential equation is derived:

Cp=Ae-ᵃᵗ+Be-ᵇᵗ

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 HALF LIFE
t1/2= 0.693/b

• From b, the regression line for the terminal exponential/b

phase is extrapolated to y axis

• Y-intercept is equal to B

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 RESIDUAL VALUES
• Values from the extrapolated line are then subtracted from
the original experimental values
• Residual plasma conc. Is obtained
• Straight line is obtained
• Residual plasma conc.

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 PARAMETERS OF THE TWO
COMPARTMENT MODEL

• Apparent volume of distribution

• Drug clearance
• Biological half life

• Elimination rate constant

• AUC

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APPARENT VOLUME OF DISTRIBUTION

• Relates plasma conc. to the amount of drug in the body

• Drugs with large extravascular distribution, apparent Vd
is generally large
• Drugs with high peripheral tissue binding also have large
apparent Vd
• For polar drugs, apparent Vd is small

• Reflects the extent of drug distribution

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 Cont.…

Several Vd are calculated as:

• Volume of central compartment
• Apparent Vd at the steady state
• Extrapolated volume of distribution
• volume of distribution by area

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VOLUME OF CENTRAL COMPARTMENT

• Useful for determining drug conc. directly after an

IV injection into the body
• Also called initial volume of distribution
• Generally smaller than the terminal Vd
• Vp as mass balance factor

• By plasma conc. and from AUC

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 Continued….
D◦=VpCp

Vp=D◦/A+B

Vp=D◦/k[AUC]

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 APPARENT VOLUME OF
DISTRIBUTION AT STEADY STATE
• The rate of drug entry into the tissue compartment
from central compartment is equal to the rate of
drug exit from tissue compartment into the central
compartment
Dtk21=Dpk12
Dt=k12Dp/k21 [Dp=CpVp]
Dt=k12.CpVp/k21

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 Cont.….

Vd=D◦/Cp

(Vd)ss=Dt+Dp/Cp

(Vd)ss=Vp(1+k12/k21)

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 Cont.….

• (VD)ss is a function of transfer constants k12 and k21

which represents rate constants of drug going into and out
of time compartment
• Magnitude of (VD)ss is dependent on:

a. hemodynamic factors for drug distribution

b. physical properties of drug

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EXTRAPOLATED VOLUME OF DISTRIBUTION

It is calculated by :
Vd=D◦/Cp

(Vd)exp=D◦/B

B=D◦(k21-b)/Vp(a-b)

(Vd)exp=Vp(a-b)/(k21-b)

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• This equation shows that a change in the distribution of
drug which is observed by change in the value for Vp, will
be reflected in change in (Vd)exp

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 VOLUME OF DISTRIBUTION BY AREA

• Reduced drug clearance from the body may

increase AUC such that (Vp)ᵦ is either reduced or
unchanged depending on the value of b.

(Vp)ᵦ=(Vd)area=Do/b[AUC]͚◦͚

Cl=Do/[AUC]͚◦
(Vd)ᵦ=Cl/b
(Vd)ᵦ=k.Vd/b

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 SIGNIFICANCE OF VOLUME OF
DISTRIBUTION
• (VD)ᵦ is affected by changes in the overall
elimination rate and by the change in the total
body clearance of the drugs

• Useful in calculation of clearance

• (Vd)exp>(Vd)ᵦ>Vp

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 Cont.….

• Changes in disease state may not result in different

pharmacokinetic parameters.
• Changes in pk parameters should not lead to the
physiologic changes.

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 DRUGS IN TISSUE COMPARTMENT

• Apparent Vt is conceptual volume only and does not

represent the true anatomic volume
Vt=Vpk12/k21

Dt=[k12Dp◦](e-ᵇᵗ_e-ᵃᵗ)/a-b

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 DRUG CLEARANCE

• Clearance is the volume of plasma that is cleared of drug

per unit time.

Cl=(Vd)b

• Useful in determining average drug conc.

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 ELIMINATION RATE CONSTANT
• Elimination rate constant of central compartment
and tissue compartment
• Because of redistribution of drug out of tissue
compartment, b is smaller than k.
• Three rate constants are associated with two
compartment model
k21=Ab+Ba/B+A
k10=ab/k21
k12=a+b-k21-k10

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 BIOLOGICAL HALF LIFE

• Biological half life can be determined from the rate

constant.

t1/2=0.693/b

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 AREA UNDER CURVE
TWO STEP METHOD:

1. Trapezoidal method
AUCt-∞=Co/ke

2. By using equation
AUCtotal=Co/k10
AUC=B/b+A/a

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 INTRAVENOUS INFUSION OF TWO
COMPARTMENT MODEL DRUGS
• I.V infusion requires a distribution and equilibrium of the
drug before the stable blood level is reached.
• Distribution equilibrium.
• Constant drug conc. in tissue.
• No net change in the amount in the tissue occurs during
steady state.
• Time needed to reach steady state blood level depends
entirely on the distribution half life of drug.

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• Equation describing plasma drug concentration:
Cp=R/Vpk[1-(k-b/a-b)e-ᵅᵗ_(a-k/a-b)e-ᵇᵗ]
• At steady state:
Css=R/Vpk
• Infusion rate:
R=CssVpk

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 LOADING DOSE FOR TWO
COMPARTMENT MODEL DRUGS

• Drugs with long half lives require a loading dose to

more rapidly attain steady state plasma drug levels
• Rapid therapeutic drug levels can be achieved by
using a loading use
• Drugs equilibrate slowly into extravasular tissues,
drug equilibrium is not immediate

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 APPARENT VOLUME OF
DISTRIBUTION AT STEADY STATE

Dtk21=Dpk12
Dt=k12Dp/k21
Dt=k12CpVp/k21

• Conc. Of drug in the central compartment at

steady state:
(Vd)ss=Dp+Dt/Cp

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(Vd)ss=CpVp+k12VpCp/k21/Cp

(Vd)ss=Vp+k12/k21Vp

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 CLINICAL APPLICATIONS
• Hydromorphone studies

• Drug distribution of Loperamide

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 CONCLUSION

• Pharmacokinetic models predict drug disposition after

drug administration.
• Statistical methods are used for the estimation and data
interpretation of pharmacokinetic parameters.
• Useful in drug formulation and treatment regimen.

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 Cont.….

• The drug behavior within the body might be able

to fit different compartmental models depending
upon the route of drug administration.

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 R
E
 N Biopharmaceutics &
Leon shargel 1941-applied
Pharmacokinetics,fifth Cedition
 Bonate P. L., Pharmacokinetic and
Pharmacodynamic modelingE and simulation, San
 PL.,
S
antion, springer online.com, 2006, p. 1-3
Madan Biopharamaceutics and
Pharmacokinetics, New Delhi: JAYPEE Bros.; 1st
ed. 2000. p. 173-193.

55
 Three compartment model and
applications of pharmacokinetic
parameters in dosage
development
 THREE COMPARTMENT MODEL
• Gibaldi & feldman described a three compartment
open model to explain the influence of route of
administration .i.e; Intravenous vs. Oral, on the area
under the plasma concentration vs. Time curve.
• Portman utilized a three compartment model which
included metabolism & excretion of
hydroxynalidixic acid.
 DRUG INPUT

DEEP
CENTRAL TISSUE TISSUE
COMPARTMENT COMPARTMENT COMPARTMENT

K10
THREE COMPARTMENT CATENARY MODEL

RAPID IV
DRUG INPUT

K21 K13
DEEP
TISSUE CENTRAL
TISSUE
COMPARTMENT COMPARTMENT
COMPARTMENT
K31
K12
DRUG OUTPUT K10

THREE COMPARTMENT MAMMILLARY MODEL

 Three compartment model consist of the following
compartments .
 Central compartment.
 Tissue compartment.
 Deep tissue compartment.

 In this compartment model drug distributes most rapidly in to first

or central compartment.
 Less rapidly in to second or tissue compartment .
 Very slowly to the third or deep tissue compartment. The third
compartment is poor in tissue such as bone & fat.
• Each compartment independently connected to the central
compartment.
• Notari reported the tri exponential equation

c=Ae-at+ Be-bt+ Ce-ct

• A,B,C are the y-intercept of extrapolated lines.
• a,b&c are the rate constants
 RAPID I.V BOLUS ADMINISTRATIONS

• When the drug is administered by IV the drug will rapidly

distributed in C.C ,less rapidly in to T.C. Very slowly in to
deep tissue compartment.
Plasma profile
• When the drug is administered by IV the plasma conc. will
increased in C.C this is first order release.
• The conc. of drug in C.C. exhibits an initial distribution
which is very rapid.
• Drug in central compartment exhibits an initial distribution
which is very rapid .
 Pharmacokinetic parameters
Bioloigical half-life ::
• It is defined as the time taken for the amount of drug in the body as
well as plasma to decline by one half or 50% its initial value.
• Concentration of drug in plasma as a function of time is
C=Ae - t+ Be -β t+ Ce -γ t
• In this equation α>β>γ some time after the distributive phase (i.e.
When time become large) the two right hand side terms values are
equal to zero.
• The eq.. Is converted in to
c=Ae-αt
Taking the natural logarithm on both sides
the rate constant of this straight line is ‘α’ and biological half life
is
t1/2 =0.693/α
 Volume of central compartment
• At time=0
C=A e –α t+ B e –β t+ C e –γ t
This equation becomes
CO = A+B+C -----1
CO =conc. Of plasma immediately after the I.V administration
• When administered dose is not distributed in tissue compartment.
• Therefore the drug is present in C.C only .
• If D is dose administered then CO = D /VC---------2
Vc=volume of drug in C.C
Combining the 1&2 eq.. We get Vc = d/Co (Co----- conc. Of drug in
plasma)
ELIMINATION RATE CONSTANT:
 Drug that follows three compartment kinetics and administered by
IV injection the decline in the plasma drug conc. is due to
elimination of drug from the three compartments.
Ke=(a+b+c) α β γ/a β γ +b α γ+ cα β
 Physiologically Based Pharmacokinetic Models
• Blood flow rate limited or perfusion rate
limited model.
• Drawn on the basis of anatomic and
physiologic data.(More realistic)
• Organs or tissues having no perfusion are
excluded.
• Drug movement to a particular region is
much more rapid than its rate of
delivery to that region by blood -
perfusion rate limited model.
• Thus, applicable to highly membrane
permeable drugs, i.e. Low molecular
weight, poorly ionized and highly
lipophilic drugs.
• For highly polar, ionized and charged
drugs, the model is referred to as
membrane permeation rate limited. 63
64
 Tissue Dosimetry
• Measure of the level of some reactive metabolites reaching
the target tissue provide a better dose parameter for risk
assessment purpose than administered doses.
• The effects of growth and ageing (since the fat increase is
proportional to the body weight, as animal grows), topical
adsorption (in inhalation studies), pregnancy and lactation
(for example changes in body weight, total body water,
plasma proteins, body fat and cardiac output will alter the
distribution of many drugs and their metabolites.) And
competitive multiple metabolites are illustrated in PBPK
modeling.

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 References :

 Biopharmaceutics and pharmacokinetics.

P L Medan, 1st edn
 Biopharmaceutics and pharmacokinetics.
D.M Brahmankar and Sunil. B .Jaiswal, 1st edn
 Applied Biopharmaceutics and pharmacokinetics
Leon shargel and Andrew Yu,
4th edn.
 Biopharmaceutics and clinical pharmacokinetics By Milo
Gibaldi, 4th edn.
 www.google.com
 www.books.google.com
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