PHARMACOKINETIC

MODELS
OVERVIE
• Basic considerationsW
in pharmacokinetics
• Compartment models
• One compartment model
• Assumptions
• Intravenous bolus administration
• Intravenous infusion
• Extravascular administration (zero order and first order
absorption model)
BASIC CONSIDERATIONS IN
PHARMACOKINETICS
• Pharmacokinetic parameters
• Pharmacodynamic parameters
• Zero, first order & mixed order kinetic
• Rates and orders of kinetics
• Plasma drug conc. Time profiles
• Compartmental models – physiological model
• Applications of pharmacokinetics
• Non compartment model
Common units in Pharmacokinetics
S.no Pharmacokinetic parameter Abbreviation Fundamental units Units example
1. Area under the curve AUC Concentration x time µg x hr/mL
2. Total body clearance ClT Volume x time Litres/time
3. Renal clearance ClR Volume x time Litres/time
4. Hepatic clearance ClH Volume x time Litres/time
5. Apparent volume of distribution VD Volume Litres
6. Vol. of distribution at steady state VSS Volume Litres
7. Peak plasma drug concentration CMAX Concentration mg/L
8. Plasma drug concentration CP Concentration mg/L
9. Steady-state drug concentration Css Concentration mg/L
10. Time for peak drug concentration TMAX Time Hr
11. Dose DO Mass mg
12. Loading dose DL Mass mg
13. Maintenance dose DM Mass mg
14. Amount of drug in the body DB Mass Mg
15. Rate of drug infusion R Mass/time mg/hr
16. First order rate constant for drug absorption Ka 1/time 1/hr
17. Zero order rate constant for drug absorption KO Mass/time mg/hr
18. First order rate constant for drug elimination K 1/time 1/hr
19. Elimination half-life t Time hr
A TYPICAL PLASMA DRUG CONC. AND TIME CURVE

8
PHARMACOKINETIC PARAMETERS

Three important parameters useful in assessing the bioavailability of a drug

from its formulation are:
1. Peak plasma concentration ( cmax )

the point at which, maximum concentration of drug in plasma.

Units : µg/ml
• Peak conc. Related to the intensity of pharmacological
response, it should be above MEC but less than MSC.
• The peak level depends on administered dose and rate of
absorption and elimination.
2. Time of peak concentration (tmax )
The time for the drug to reach peak concentration in
plasma (after extra vascular administration).
Units : hrs
• Useful in estimating onset of action and rate of absorption.
• Important in assessing the efficacy of single dose drugs used to treat
acute conditions (pain, insomnia ).
3. Area under curve (AUC)
It represents the total integrated area under the plasma level-time profile and
expresses the total amount of the drug that comes into systemic circulation
after its administration.
Units : µg/ml x hrs
• Represents extent of absorption – evaluating the bioavailability of drug from its
dosage form.
• Important for drugs administered repetitively for treatment of chronic
conditions (asthma or epilepsy).
PHARMACODYNAMIC
PARAMETERS
1. Minimum effective concentration (MEC)
Minimum concentration of drug in plasma/receptor site required to produce
therapeutic effect.
• Concentration below MEC – sub therapeutic level
• Antibiotics - MEC
2. Maximum safe concentration (MSC)
Concentration in plasma above which adverse or unwanted effects are
precipitated.
• Concentration above MSC – toxic level
3. Onset time
Time required to start producing pharmacological response.
Time for plasma concentration to reach mec after administrating drug
4. Onset of action
The beginning of pharmacologic response.
It occurs when plasma drug concentration just exceeds the required mec.
5. Duration of action
The time period for which the plasma concentration of drug remains above
MEC level.
6. Intensity of action
It is the minimum pharmacologic response produced by the peak plasma conc.
Of drug.
7. Therapeutic range the drug conc. Between MEC and MSC
CONCEPT OF “HALF LIFE”
 ½ Life = how much time it takes for blood levels of drug to decrease to
half
of what it was at equilibrium
 There are really two kinds of ½ life…
 “Distribution” ½ life = when plasma levels fall to half what they were
at equilibrium due to distribution to/storage in body’s tissue reservoirs.
 “Elimination” ½ life = when plasma levels fall to half what they
were at equilibrium due to drug being metabolized and eliminated.
 It is usually the elimination ½ life that is used to determine dosing
schedules, to decide when it is safe to put patients on a new drug.
PHARMACOKINETIC MODELS AND
COMPARTMENTS
Pharmacokinetic Modelling

Compartmen Non-Compartment Physiologic

t Models Models
Models

AUC, MRT, MAT, Cl, VSS

Caternary Mamillary
Model Model

One compt Multi compt Two compt

iv
bolus i v bolus
Single oral
Dose
iv
infusion Oral
Intermittent i v infusion
drug
Multiple
PHARMACOKINETIC MODELS
 Means of expressing mathematically or quantitatively, time course of drug
through out the body and compute meaningful pharmacokinetic parameters.
Useful in :
• Characterize the behavior of drug in patient.
• Predicting conc. Of drug in various body fluids with dosage regimen.
• Calculating optimum dosage regimen for individual patient.
• Evaluating bioequivalence between different formulation.
• Explaining drug interaction.
Pharmacokinetic models are hypothetical structures that are used to describe the
fate of a drug in a biological system following its administration.
Model
• Mathematical representation of the data.
• It is just hypothetical
WHY MODEL THE DATA ?

There are three main reasons due to which the data is subjected to modelling.
1. Descriptive: to describe the drug kinetics in a simple way.
2. Predictive: to predict the time course of the drug after multiple dosing
based on single dose data, to predict the absorption profile of the drug
from the iv data.
3. Explanatory: to explain unclear observations.
PHARMACOKINETIC MODELING IS
USEFUL IN :-
• Prediction of drug concentration in plasma/ tissue/ urine at any point of
time.
• Determination of optimum dosage regimen for each patient.
• Estimation of the possible accumulation of drugs/ metabolites.
• Quantitative assessment of the effect of disease on drug’s adme.
• Correlation of drug concentration with pharmacological activity.
• Evaluation of bioequivalence.
• Understanding of d/i.
COMPARTMENTAL MODELS
• A compartment is not a real physiological or anatomic region
but an imaginary or hypothetical one consisting of tissue/
group of tissues with similar blood flow & affinity.
• Our body is considered as composed of several
compartments connected reversibly with each other.
ADVANTAGES
• Gives visual representation of various rate processes involved in
drug disposition.
• Possible to derive equations describing drug concentration changes in
each compartment.
• One can estimate the amount of drug in any compartment of the
system after
drug is introduced into a given compartment.
DISADVANTAGES
• Drug given by IV route may behave according to single compartment
model
but the same drug given by oral route may show 2 compartment
behaviour.
• The type of compartment behaviour i.E. Type of compartment model
may change with the route of administration.
TYPES OF
COMPARTMENT
1. Central compartment
Blood & highly perfused tissues such as heart, kidney, lungs, liver, etc.
2. Peripheral compartment
Poorly per fused tissues such as fat, bone, etc.
MODELS:
“OPEN” and “CLOSED” models:
• The term “open” itself mean that, the administered drug dose is removed from
body by an excretory mechanism ( for most drugs, organs of excretion of drug is
kidney)
• If the drug is not removed from the body then model refers as “closed” model.
ONE COMPARTMENT MODEL
 One compartment model can be defined :
• One com. Open model – i.V. Bolus.
• One com. Open model - cont. Intravenous infusion.
• One com. Open model - extra vas. Administration (zero-order
absorption)
• One com. Open model - extra vas. Administration (First-order
absorption )
• INTRAVENOUS (IV) BOLUS ADMINISTRATION
RATE OF DRUG PRESENTATION TO BODY
IS:
• Dx/dt =rate in (availability)–rate out( Eli)

• Since rate in or absorption is absent, equation

becomes dx/dt = - rate out
• If rate out or elimination follows first order kinetic
Dx/dt = -kex (eq.1)
ELIMINATION PHASE:
 Elimination phase has three parameters:
• Elimination rate constant
• Elimination half life
• Clearance
ELIMINATION RATE CONSTANT
• Integration of equation (1)
• In x = ln xo – ke t
Xo (eq.2)
= amt of drug injected at time t = zero i.E. Initial amount of drug injected
X=xo e-ket ( eq.3)
• Log x= log xo – ke t
2.303 (eq.4)

• Since it is difficult to directly determine amount of drug in body x, we use relationship

that exists between drug conc. In plasma C and X; thus
• X = vd C (eq. 5)
• So equation-8 becomes
log c = log co –
ke t 2.303 (eq.6)
KE = KE + KM +KB +KL +….. (Eq.7)
(KE is overall elimination rate constant)
ELIMINATION HALF LIFE

T1/2 = 0.693
KE

(eq.8)
• Elimination half life can be readily obtained from the graph of log
c versus t
• Half life is a secondary parameter that depends upon the primary
parameters such as clearance and volume of distribution.
• T1/2 = 0.693 V d
Cl T (eq.9)
APPARENTVOLUME OF
DISTRIBUTION
• Defined as volume of fluid in which drug appears to be
distributed.
• Vd = amount of drug in the body x
= Plasma drug concentration C (eq.10)

Vd = xo/co
=I.V.Bolus dose/co
(eq.11)
• Vol.
Example: 30=mg
Of dist. i.V. Bolus, plasma conc.= 0.732
30mg/0.732mcg/ml mcg/ml.
=30000mcg/0.732mcg/ml
= 41 liter.
• For drugs given as i.V.Bolus,
Vd (area)=xo/KE.Auc …….12.A
• For drugs admins. Extra. Vas.
Vd (area)=f xo/ke.Auc ……..12.B
CLEARANCE
Clearance = rate of elimination
Plasma drug conc.. (Or) cl= dx /dt

C ……., (eq.13)
Thus, renal clearance = rate of elimination by
kidney
C
Hepatic clearance =
rate of elimination by
liver
Other organ clearance = rate of eliminationCby organ

C
Total body clearance:
Clt = clr + clh + clother ……, (eq.14)
• According to earlier definition
cl = dx /dt
C
• Submitting eq.1 dx/dt = KE X , above eq. Becomes ,clt = KE X/ C .., (Eq
15)
• By incorporating equation 1 and equation for vol. Of dist. ( Vd= X/C ) we can
get
clt =KE vd (eq.16)
• Parallel equations can be written for renal and hepatic clearance.
Cl =km vd
h (eq.17)

Clr =ke vd (eq.18)

• But, KE= 0.693/t1/2

• So, clt = 0.693 (eq.19)

vd
t1/2
• For non compartmental method which follows one
compartmental kinetic is :
• For drug given by i.V. Bolus

clt = xo
Auc
…..20.A
• For drug administered by e.V.
Clt = f xo …..20.B
Auc
• For drug given by i.V. Bolus
renal clearance = xu∞ …….(eq. 21)

auc
ORGAN CLEARANCE
• Rate of elimination by organ= rate of presentation to the organ – rate of
exit from the organ.

• Rate of elimination =Q. Cin- Q.Cout

(Rate of extraction) =Q (cin-
cout)
Clorgan=rate of extraction/cin
=Q.Er …………….(eq 22)
=Q(cin-cout)/cin
• Extraction ratio:
ER= (cin- cout)/ cin
• ER is an index of how efficiently the eliminating organ clear the
blood
flowing through it of drug.
 According to ER, drugs can be classified as
• Drugs with high ER (above 0.7)
• Drugs with intermediate ER (between 0.7-0.3)
• Drugs with low ER (below 0.3)

• The fraction of drug that escapes removal by organ is expressed

as F= 1- ER
• Where f=systemic availability when the eliminating organ is liver.
HEPATIC CLEARANCE

For some drugs,

The non renal clearance is equal to hepatic clearance.
Clh = clt – clr
 Can also be written down from eq 22
ClH= QH ERH
 QH= hepatic blood flow (1.5 L/min).
 ERH = hepatic extraction ratio.
 Hepatic clearance of drug can be divided into two groups :
HEPATIC CLEARANCE
1. Drugs with hepatic blood flow rate-limited clearance
When ERH is one
ClH approaches its maximum value i.e hepatic blood flow.
ClH= QH
• Hepatic clearance said to be perfusion rate limited/ flow
dependent.
• Alteration in hepatic blood flow affects elimination of
drugs with high ERH
Example: Propanolol, Lidocaine
(Removed from blood as they are presented to the liver)
HEPATIC CLEARANCE

Hepatic blood flow has very little/no effect on drug with low
ERH

Whatever concentration of drug present in the blood perfuses

liver, is always more than what the liver can eliminate (low first
pass hepatic metabolism)

Ex: Theophylline
HEPATIC BLOOD FLOW
2. INTRINSIC CAPACITY CLEARANCE
• Denoted as Clint, it is defined as the

“Inherent ability of an organ to irreversibly remove a

drug in the absence of any flow limitation."
• Depends on enzyme activity.

• Drugs with low ERH and with elimination primarily

by metabolism are greatly affected by changes in
enzyme activity.
• Hepatic clearance of such drugs is said to be
capacity limited.

Example: Theophylline
INTRINSIC CAPACITY CLEARANCE
ONE COMPARTMENT OPEN MODEL:
INTRAVENOUS INFUSION
• Model can be represent as : ( i.v infusion)

Drug R0 Blood & other KE

Body Elimination
Zero order
Infusion tissues
rate

Dx/dt =Ro-kex …eq 23

X=Ro/ke(1-e-ket) …eq 24
Since X =vdc
C= Ro/kevd(1-e-ket) …eq 25

= Ro/clt(1-e-ket) …eq
26
• At steady state. The rate of change of amount of drug in the body is zero ,eq
23 becomes
Zero=Ro-kexss …27
Kexss=Ro …28
Css=Ro/kevd …29

=Ro/Clt i.e infusion rate ....30

Clearance
Substituting eq. 30 in eq.
26 …31
• C=Cs
(1-e-ket)
s ...32
Rearrangement
C yields:
ss
• [Css-c]=e-ket . = -ket …33
Log CSS-C
2.303
Css
• If n is the no. Of half lives passed since the start of infusion(t/t1/2)
• Eq. Can be written as

• C=CSS [1-(1/2)n] …34

INFUSION PLUS LOADING
DOSE

…35
XO,L=CSSVD Equation for computing the loading dose X0,L
INFUSION PLUS LOADING
DOSE
SUBSTITUTION OF CSS=RO/KEVD form eq 29
XO,L=RO/KE …36

C=XO,L/VD e -KET+ RO/KEVD(1-e-KET) …37

ONE COMPARTMENT OPEN MODEL
EXTRA VASCULAR ADMINISTRATION
• When drug administered by extra vascular route (e.G. Oral, i.M,
rectal ),
absorption is prerequisite for its therapeutic activity.
ONE COMPARTMENT MODEL: EXTRA
VASCULAR ADMIN ( ZERO ORDER
ABSORPTION)
• This model is similar to that for constant rate
infusion.
Drug at site
R0 Blood & other zero order elimination
Body
Absorptio tissues
o Rate of drug absorption as in casenof CDDS , is constant and continues
until the amount of drug at the absorption site (Ex. GIT) is depleted.
o All equations for plasma drug conc. Profile for constant rate i.V. Infusion
are also applicable to this model.
ONE COMPARTMENT MODEL: EXTRA
VASCULAR ADMIN ( FIRST ORDER
ABSORPTION)
• Drug that enters the body by first order absorption process gets distributed
in the body according to one compartment kinetic and is eliminated by first
order process.
• The model can be depicted as follows and final equation is as follows

C=Ka F Xo/Vd (Ka-KE) [e -Ket-e-Kat] …41

Ka KE
Drug at Blood & other elimination
site First order Body tissues

absorption
MULTI- COMPARTMENT
MODELS
• Ideally a true pharmacokinetic model should be the one with a rate constant for
each tissue undergoing equilibrium.
• Therefore best approach is to pool together tissues on the basis of similarity in
their distribution characteristics.
• The drug disposition occurs by first order.
• Multi-compartment characteristics are best described by administration as i.v
bolus and observing the manner in which the plasma concentration declines with
time.
The no. Of exponentials required to describe such a plasma level-time profile
determines the no. Of kinetically homogeneous compartments into which a
drug will distribute.
The simplest and commonest is the two compartment model which classifies the
body tissues in two categories :
1. Central compartment or compartment 1
2. Peripheral or tissue compartment or compartment 2.
TWO COMPARTMENT OPEN MODEL-IV
Elimination from central compartment
BOLUS
Fig: ADMINISTRATION:
1 2
Central peripheral

• After the iv bolus of a drug the decline in the plasma conc. Is bi-
exponential.
• Two disposition processes- distribution and elimination.
• These two processes are only evident when a semi log plot of C vs. T is
made.
• Initially, the conc. Of drug in the central compartment declines rapidly, due
to the distribution of drug from the central compartment to the peripheral
compartment. This is called distributive phase.
Extending the relationship X= vd C

Dcc = K21 xp – K12 xc – KE xc

Dt vp vc vc
X= Amt. Of drug in the body
at any time t remaining to be
eliminated
C=drug conc in plasma
Vd =proportionality const
app. Volume of distribution
=
Xc and xKp12 xc – K
=amt xp in C1
of21drug
V vp On integration equation gives conc of drug in central and
andperipheral
C2 c compartments at any given time t
Vc and vp=apparent volumes
of C1 and C2Cp = xo [( ) ( ) ]
K21 – a e-at + K12 – b e-bt

Vc
Xo = iv bolus dose b–a a–b
• The relation between hybrid and microconstants is given as :
a + b = K12 + K21 +
KE A b = K21 KE
Cc = a e-at + be-bt
Cc=distribution exponent
+ elimination
e
x
p
A = X0 [K21 - A] = CO [K o21 – A]
VC B–A n–A
B
e
n
B = X0 [K 21 - B] = C O t 21 – B]
[K
VCare hybrid
A and B A – B constants for
A –two
B exponents and can be resolved by
graph by method of residuals.
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.
C = a e-at + b e-bt
From graph the initial decline due to distribution is more rapid than the terminal
decline due to elimination i.E. The rate constant a >> b and hence the term e-at
approaches zero much faster than e –bt
C = B e-bt
Log C = log B – bt/2.303 C = back extrapolated pl. Conc.
• A semilog plot of C vs t yields the terminal linear phase of the curve having
slope –b/2.303 and when back extrapolated to time zero, yields y-intercept log
B. The t1/2 for the elimination phase can be obtained from equation
• t1/2 = 0.693/b.
• Residual conc values can be found as-
Cr = C – C = ae-at
Log cr = log A – at
2.303
A semilog plot cr vs t gives a straight line.
Ke = abc
Ab+Ba
K12 = a b (b - a)2
C0 (A b + B a)
K21 = Ab + Ba
C0
• For two compartment model, KE is the rate constant for elimination of drug
from the central compartment and b is the rate constant for elimination
from the entire body. Overall elimination t1/2 can be calculated from b.
Area under (auc) = a+b
The curve a b
App. Volume of central = X0 = X0
compartment C0 KE (AUC)
App. Volume of = VP = VC K12
Peripheral compartment K21
Apparent volume of distribution at steady state or equilibrium
Vd,ss = VC +VP
Vd,area = X0
B AUC
Total systemic clearence= clt = b vd
Renal clearence= clr = dxu = K E VC
Dt

The rate of excretion of unchanged drug in urine can be represented

by : dxu = KE A e-at + KE B e-bt
Dt
The above equation can be resolved into individual exponents by the
method of residuals.
TWO – COMPARTMENT OPEN
1 MODEL- I.V.2

INFUSION
Central Peripheral

The plasma or central compartment conc of a drug when administered as constant rate (0 order) i.V. Infusion is
given as:

C = R0 [1+(KE - b)e-at +(KE - a)e-bt]

VC KE b–a a-b

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

Css = R0

Vc ke

Now VC KE = vd b

Css = r0 = r0

V
db
clt

The
TWO-COMPARTMENT OPEN
• FirstMODEL-
- order absorption EXTRAVASCULAR
:
• For aADMINISTRATION
drug that enters the body by a first-order absorption process and
distributed according to two compartment model, the rate of change in drug
conc in the central compartment is described by three exponents :
• An absorption exponent, and the two usual exponents that describe drug
disposition.
The plasma conc at any time t is
C = n e-kat + l e-at + m e-bt

C = absorption + distribution + elimination

Exponent exponent exponent
• Besides the method of residuals, ka can
also be found by loo-riegelman method
for drug that follows two-compartment
characteristics.
• Despite its complexity, the method can be applied to drugs that distribute in any
number of compartments.
CALCULATING Ka using Wagner-
nelson method(Bioavailability
parameters)
WAGNER-NELSONS METHOD
THEORY: The working equations can be derived from the mass balance
equation: Gives the following eqaution with time and mass balance

• Above equation Integrating

gives
• To the equation amount
absorbed VERSUS TIME
WAGNER-NELSONS METHOD
• Taking this to infinity where cp equals 0

• Finally (Amax - A), the amount remaining to be absorbed can also be

expressed as the amount remaining in the GI, xg
• We can use this equation to look at the absorption process. If, and only
if, absorption is a single first order process
WAGNER-NELSONS METHOD
• Example data for the method of wagner-nelson kel (from IV data) = 0.2 hr-
Time Plasma Column Column Column 5 A/V (Amax - A)/V
Concentratio 3 4 kel * [Col2 +
(hr) n ΔAUC AUC AUC Col5]
(mg/L)
0.0 0.0 0.0 0.0 0.0 0.0 4.9

1.0 1.2 0.6 0.6 0.12 1.32 3.58

2.0 1.8 1.5 2.1 0.42 2.22 2.68

3.0 2.1 1.95 4.05 0.81 2.91 1.99

4.0 2.2 2.15 6.2 1.24 3.44 1.46

5.0 2.2 2.2 8.4 1.68 3.88 1.02

6.0 2.0 2.1 10.5 2.1 4.1 0.8

8.0 1.7 3.7 14.2 2.84 4.54 0.36

10.0 1.3 3.0 17.2 3.44 4.74 0.16

12.0 1.0 2.3 19.5 3.9 4.9 -

∞ 0.0 5.0 24.5 4.9 4.9 -

WAGNER-NELSONS METHOD
• The data (Amax-A)/V versus time can be plotted on semi-log and linear
graph paper
WAGNER-NELSONS METHOD
• Plotting (Amax-A)/V versus time produces a straight line on semi-log graph paper and a
curved line on linear graph paper. This would support the assumption that absorption can be
described as a single first process. The first-order absorption rate constant, ka, can be
calculated to be 0.306 hr-1 from the slope of the line on the semi-log graph paper.

ADVANTAGES:

• The absorption and elimination processes can be quite similar and accurate determinations of
ka can still be made.

• The absorption process doesn't have to be first order. This method can be used to investigate
the absorption process.

DISADVANTAGES:

• The major disadvantage of this method is that you need to know the elimination rate constant,
from data collected following intravenous administration.

• The required calculations are more complex.

RESIDUAL METHOD OR
FEATHERING TECHNIQUE
• Absowhen a drug is administered by extravascular route, absorption is a
prerequisite for its therapeutic activity.

• The absorption rate constant can be calculated by the method

of residuals.

• The technique is also known as feathering, peeling and stripping.

φ It is commonly used in pharmacokinetics to resolve a
multiexponential curve into its individual components.

φ For a drug that follows one-compartment kinetics and

administered extravascularly, the concentration of drug
in plasma is expressed by a biexponential equation.

𝐾𝑎𝐹𝑋0
C= [e-KEt – e-Kat]
(1)
𝑉𝑑(𝐾𝑎−𝐾𝐸)

If KaFX0/Vd(Ka-KE) = A, a hybrid constant, then:

C = A e-KEt – A e-Kat (2)
φ During elimination phase, when absorption is
the over, Ka<<KE and the value of
almost second e-Kat approaches zero whereas the
exponential
first exponential e-KEt retains some finite value.

φ At this time, the equation (2) reduces to:

𝐶− = 𝐴 𝑒− 𝐾𝐸𝑡(3)

φ In log form, the above equation is:

𝐾𝐸𝑡
Log C− = log A - (4)
2.30
3
Where ,
C− = back extrapolated plasma concentration values

φ A plot of log C versus t yield a biexponential curve with a

terminal linear phase having slope –KE/2.303

φ Back extrapolation of this straight line to time zero yields y-

intercept equal to log A.

70
Plasma conc.-Time profile after oral administration of a single dose of a drug
φ Subtraction of true plasma concentration values i.e.
equation (2) from the extrapolated plasma
concentration values i.e. equation (3) yields a series
of residual concentration value Cτ.

(C− - C) = Cτ = A e-Kat(5)

φ In log form , the equation is:

𝐾𝑡
log Cτ= log A - 2.30
𝑎
(6)
3
φ A plot of log Cτ versus t yields a straight line with slope -
Ka /2.303 and y-intercept log A.

φ Thus, the method of residual enables resolution of the

biexponential plasma level-time curve into its two
exponential components.

φ The technique works best when the difference between

Ka and KE is large (Ka/KE ≥ 3).
THREE COMPARTMENT MODEL
AND APPLICATIONS OF
PHARMACOKINETIC
PARAMETERS IN DOSAGE
DEtfELOPMENT
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 hydroxy nalidixic acid.
DRUG INPUT

DEEP
CENTRAL TISSUE TISSUE
COMPARTMEN COMPARTMEN COMPARTM
T T ENT

K10

THREE COMPARTMENT CATENARY MODEL

RAPID IV
DRUG INPUT

K21 K13
DEEP
TISSUE CENTRAL
TISSUE
COMPARTMEN COMPARTMEN
COMPARTMEN
T T K31 T
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=a e-t+ b e-βt+ c e-γt
• A,B,C are the y-intercept of extrapolated
lines.
• Α,β,γ are the rate constants
RAPID I.V BOLUS
ADMINISTRATIONS
• When the drug is administered by i.V 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 i.V the plasma conc. Will increased in c.C
this is first order release.
• The conc. Of drug in c.C. Exhibits an initial distribution this is very rapid.
• Drug in central compartment exhibits an initial distribution this 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=a e - t+ b e -β t+ c e -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=a e-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 the dose is not
distributed in tissue compartment.
• Therefore the drug is present in c.C
only .
• If D is dose administered then CO = D /V C---------2
Vc=volume of drug in c.C
Combining the 1&2 eq.. We get Vc = d/co (c o-----
conc. Of drug in plasma)
ELIMINATION RATE CONSTANT:
 Drug that follows three compartment kinetics and administered by i.V injection the
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 81
membrane permeation rate limited.
82
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
increasing 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 modelling. 83
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