A SEMINAR ON

by

V. Sandeep Kumar
M.Pharmacy, I Sem.

Department of Pharmaceutics
University College Of Pharmaceutical Sciences
Kakatiya University
Warangal

CONTENTS
Introduction
Methods To Detect Absorption Rate Constant

Method of Residuals
Wagner-Nelson Method
Loo - Riegelman Method
Deconvolution Method
Estimation of ka from Urinary Data

Significance of Absorption Rate Constants

Conclusion
References

INTRODUCTION
Absorption can be defined as the process of movement of
unchanged drug from site of administration to site of
measurement i.e plasma.
The actual drug absorption process may be zero-order, firstorder, or a combination of rate processes that is not easily
quantitated.

METHOD OF RESIDUALS
The technique is also known as feathering, peeling and stripping.

For a drug that follows one-compartment kinetics and

administered extra vascularlly, the time course of drug

concentration in plasma is expressed by a bi exponential
equation 1.

Equation-1

Equation 1 can be written as

Cp = A.e-kel.t A.e-ka.t

Equation- 2
where

Cp

True plasma
concentration
values

Time(hours)

Figure 1. Semi-log
plot of Cp versus
Time after Oral
Administration

During the elimination phase, when absorption is almost over,( Ka

>> Kel ) and the value of second exponential approaches zero (ekat) whereas the first exponentional (e-ket ) retains some finite
value.
At this time, the equation 2 reduced to
Cp = A.e-kel.t

equation -3

where cp represents the back extrapolated plasma concentration

values.
A plot of log cp verses t gives terminal linear phase having slope =
-kel /2.303.
Back extrapolation of this straight line to time zero yields
y-intercept equals to=log A

log C= log[
Intercept

KaFX 0
] Kt / 2.303
Vd ( Ka K )

Back extrapolation terminal portion of

curve logCp

Cp

Slope =- kel /2.303

Time(hours)
Figure 2. Semi-log Plot of Cp versus Time after oral
administration of single dose

Substracting of true plasma concentration values i.e.

equation 2 from extrapolated plasma concentration values i.e.
equation 3 yields a series of residual concentration values .
Cr = cp- cp
Cr = A.e ka t

equation 4

Plotting the Cr versus time should give another straight

line graph with a slope equal to ka/2.303 and the same
intercept as before, i.e. log A

log C log[

Intercept=

KaFX 0
] Kt / 2.303
Vd ( Ka K )

Back extrapolated terminal portion of curve

Residual curve

Cp

True plasma concentration values

Slope=- ka/2.303

Time(hours)
Figure 3. Semi-log Plot of Cp versus Time

Slope= -kel/2.303

From the slope, the absorption rate constant Ka

estimated..

can be

In this method of calculation it is important to remember

that the following assumptions are made:
1. It is assumed that ka is at least five times larger than k el, if not
neither constant can be determined accurately.
2. It is assumed that the absorption and elimination processes
both follow the first order, if not the residual line and, perhaps,
the elimination line will not be straight.

LAG TIME
The time delay prior to the commencement of the first order

drug absorption is known as Lag time( t 0 ).

In some instances absorption of drug a single oral dose not
started immediately due to such physiological factors as
stomach-emptying time and intestinal mobility or due to
formulation itself.
where Fk aD 0/V D(k ak) is the y
value at the point of intersection of
the residual lines in .
where A and B represents the
intercepts after extrapolation of the
residual lines for absorption and
elimination, respectively.

Plasma drug level

Back extrapolated terminal portion of curve

Residual curve

Lag time t0

Time(hours)

Figure 4. Determination of lag time by graphically

Flip-Flop of ka and kel

The estimation of the rate constant for absorption and

elimination by method of residuals is based on the assumption

that ka>>kel.
If kel >> ka, then the values of ka from the terminal phase and
kel from the residual line are obtained .
This phenomenon is called flip-flop of the absorption and
elimination rate constant.
The only way to be sure of estimates is to compare kel
calculated from oral administration with kel from intravenous
data

METHOD OF RESIDUALS FOR TWO

COMPARTMENT MODEL

There are three first order processes occurring simultaneously

i.e. absorption, distribution and elimination
Plasma concentration of the drug depends initially on three
process (three exponents), then on two processes of distribution
and elimination (two exponentials) and finally on elimination
process only ( mono exponential).
C = C0 e-kat + A e-t + B e-t

Log CO
True plasma concentration curve

Log A

Back extrapolated distribution curve

Log B

Back extrapolated elimination curve

First residual curve
Second residual curve

Slope=-/2.303
Log C
Slope=-ka/2.303

Time(hours)

Figure 5

Slope=-/2.303

APPLICATIONS
To

calculate absorption rate constant for a drug administered

orally ,absorbed by first order kinetics and confer the
characteristics of one and two compartment open model .
For a drug following intravenous administration and confer
multy compartmental characteristics .

LIMITATIONS
When the absorption is complex rather than a simple first order
process .

WAGNER-NELSON METHOD
The Wagner-Nelson method of calculation does not require a model
assumption concerning the absorption process
The assumptions are
(1) The body behaves as a single homogeneous compartment,
(2) Drug elimination obeys the first order kinetics.

For any e.v administration,

The amount administered = The amount absorbed (A)+ The
Amount unabsorbed (U)

The amount absorbed (A) to any time t = the amount of the drug
in the body (X) + the amount of the drug eliminated from the
body to any time, t (Xe)
A = X + Xe
6
Taking the derivative with respective time
dA/dt = dX/dt + dXe/dt
7
but X = Vd. C ,hence
dX/dt = Vd. dC/dt
and
therefore,

dXe/dt = KX therefore,
dXe/dt = K.Vd.C

dA/dt = Vd. dC/dt + K.Vd.C

dA = Vd.dC + K.Vd.C.dt

integrating equation 8 between limits of t = 0 to t = t gives,

t

dA Vd dC K.Vd . C. dt
t

At A0 Vd Ct C0 K.Vd C. dt
0

A0 = amount of drug absorbed at t = 0 is zero ,& C0 =0. so,

t

At Vd . Ct KVd
. C. dt
0

Rearranging the above equation

At
Ct K . C. dt
Vd
0

Where At/Vd is the amount of drug absorbed up to time t divided

by the volume of distribution
Ct = plasma concentration at time t
t

At
Ct K . C. dt
d
0

= AUC up to time t.
Integrating equation 8 between the limits of t = 0 to t =
And rearranging the equation, give the following

dA Vd dC K.Vd . C. dt

A Vd . C C0 K.Vd . C. dt

but C = 0, C 0= 0

10

Where, A/Vd = the total amount of drug absorbed from the dosage
form up to infinity time divided by the volume of the distribution of
the drug.

C. dt

= AUC up to

The fraction of absorbed at any time is obtained when equation 9 is

divided by equation 10
t

Ct K C. dt

0
At / A

K Cdt

11

the fraction of unabsorbed at any time t is

12

figure 7

Slope=absorption
rate constant

Time(hours)

Percent of unabsorbed
drug versus time plot-Zero
order

Log Percent of unabsorbed

Percent of unabsorbed

figure 6

Slope=-ka/2.303

Time(hours)

Logarithm Percent of
unabsorbed drug versus
time plot-First order

Wagner Nelson Method Procedure

1.
2.
3.
4.
5.
6.
7.

Plot log concentration of drug versus time.

Find K from the terminal part of slope when the slope is
K/2.303.
Find AUCt0 by plotting Cp versus time.
Find K.AUCtO by multiplying each AUCtO by K.
Find AUC0 by adding up all the AUC pieces, from t = 0 to t
= .
Determine the 1-(Ab/Ab) value corresponding to each time
point using by the table.
Plot 1-(Ab/Ab) versus time on semi log paper, with 1(Ab/Ab)on the logarithmic axis.

For Example

k = 0.1 hr 1

APPLICATIONS
To understand the absorption kinetics without prior assumption .
Two formulations of a drug that differ substantially in terms of
how much of drug is eventually absorbed which is reflected in
t

At
Ct K . C. dt
Vd
0

Vs time plots

LIMITATIONS
It applies rigorously only to the drugs with one compartmental
characteristics .
However , when conc vs time curve after oral administration
shows multi compartmental characteristics and on IV
administration shows one compartmental model, analysis by
this method gives incorrect result

LOO-RIEGELMAN METHOD
Loo -Riegelman method is useful in determining the absorption

rate constant for a drug follows a two compartment model.

It requires the plasma concentration time data after i.v. bolus

and oral administration to obtain all necessary kinetic

constants.
This method can be applied to drug that can distributed by any

number of compartments

Ab = Xc +Xt +X3

Equation 3.1

Xc = Vc.Cp
Xt = Vt.Ct
X3 = Vc.k13 C.dt = Vc.k13 .[AUC]0t
Substituting of Xc and X3 into equation 3.1
Ab = Vc.Cp + Xt + Vc.k13 .[AUC]0t

Equation 3.2

 Dividing the equation 3.2 by Vc, we get

Ab/ Vc= Cp + Xt/Vc + K13 [AUC]0t Equation 3.3

Setting the value of t = , this equation becomes
Ab /Vc = 0+ 0 + K13 [AUC]0
Ab /Vc = K13 [AUC]0

Equation 3.4

Where, Ab is the amount of the drug that will be ultimately

absorbed from the dosage form.

F = Ab /X0

Equation 3.5

 The fraction of the dose absorbed at any time in comparison with

Ab can be obtained by dividing the equation 3.3 by equation 3.4.

Slope= -Ka/2.303

equation3.6
Where, Xt /Vc = Ct = tissue
concentration

figure 8
Absorption rate constant by
Loo- Riegelman method

Equation 3.7
Where
Ct= Apparent tissue concentration
tn= time of sampling for sample n
tn-1 = time of sampling for the sampling point preceding sample n
(Cp) tn-1 = concentration of drug at central compartment for
sample n-1
Cp = concentration difference at central compartment between
two sampling times.
t = Time difference between two sampling times.

Example To Calculate Ct values

K=0.16 hr 1 ,k 12 = 0.29 hr 1, k 21 = 0.31hr 1.

APPLICATIONS
Loo Riegelman method is applicable for the drugs that confers
multi compartmental characteristics .

LIMITATIONS
It requires the concentration vs time data of both oral and IV
administration ofdrug to same subject.
An inherent limitation of this method is intra subject variability
between oral and IV administration studies . The assumption be
made that kinetics of drug distribution and elimination remain
unchanged in interval between doses.

DECONVOLUTION METHOD
It is a model independent method for determining the
absorption rate and its use has been limited.
It requires no assumptions regarding the no of compartments
or kinetics of absorption .
Linear distribution and elimination are assumed.
It require both the data after oral and IV administration in
same subject .

ESTIMATION Ka FROM URINARY DATA

Using a plot of percent of drug unabsorbed versus time.
For a one-compartment model

Ab =DB+DE

5.1
5.2

Assuming first-order elimination kinetics with renal elimination

constant k e
5.3
5.4

Rearranging Equation 5.3

Assuming a one-compartment model,
Substituting V D C p into Equation 5.2

5.5

Substituting for dC p/ dt into Equation 5.5 and kDu/ k e for D E,

5.6

When the above expression is integrated from zero to time t,

At t = . The total amount of drug absorbed is Ab and dD u/ dt = 0

D u - total amount of
unchanged drug excreted in the
urine.
The fraction of drug absorbed at
any time t

Slope= -Ka/2.303

figure 9

LIMITATIONS
If the drug is rapidly absorbed, it may be difficult to obtain
multiple early urine samples to describe the absorption phase
accurately.
Drugs with very slow absorption will have low
concentrations.

SIGNIFICANCE OF ABSORPTION RATE CONSTANT

The calculation of k a is useful in designing a multiple-dosage

regimen. Knowledge of the k a and k allows for the prediction

of peak and trough plasma drug concentrations following
multiple dosing
The peak time (t max) in the plasma conc. versus time curve
provides a convenient measure of absorption rate.
With the increase in absorption rate constant, C max also
increases.

Effect of a change in the absorption rate constant, k a, on the

plasma drug concentration-versus-time curve.

CONCLUSION
To compare different formulations of same drug.
The method of residual is used for the drugs which follow one
or multi compartmental characteristics but the absorption process
should not be complex .
Wagner nelson method is used for the drug confers one
compartmental characteristics by orally.
Loo Riegelman method is applicable for the drug that confers
multi compartmental characteristics .
Deconvolution method has limited use due to its complexity.
When there is lack of sufficiently sensitive analytic techniques
to measure concentration of drugs in plasma, urinary excretion
data is used.

REFERENCES
1. Leon Shargel, Susanna, Wu Pong, Andrew B.C.Yu, Applied Biopharmaceutics and
Pharmacokinetics, Fifth Edition, Mc Graw Hill., pp.161-182.
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Applications, third edition,Waverly.,pp.119-130,478-484.
3. Milo Gibaldi and Donald Perrier, Pharmacokinetics; Second edition volume. 15,
Marcel dekker., pp33-36,145-167,433-444.
4. V. Venkateshwarlu., Biopharmaceutics and pharmacokinetics, Pharma Book
syndicate.,pp.221-224,259-263,385-387.
5. D.M.Brahmankar, SunilB.Jaiswal, Biopharmaceutics and pharmacokinetics ,a
Treatise,pp.222-224,244-268,
6. www.australianprescriber.com
7. www.ncbi.nlm.nih.gov
8. www.boomer.org
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