312 views

Uploaded by Filip Ilievski

information on determination of absorption constants by the method of residuals, wagner nelson model etc.

- Chapter 11-Homogeneous Reaction
- Chemistry and Differential Equations
- Pharmacokinetic models
- Ladmer System
- b001Validation and Evaluation of Linguistic Logics
- b001Validation and Evaluation of Linguistic Logics
- EMEA - Summary of the Product Characteristics
- Physical Chemistry Chapter 11 3 Atkins
- pH
- lec25.pdf
- 0 - Introduction.pdf
- Compartment Modeling
- Ece4343 Week 3 s
- DRUG INTERACTION bu'azizah.ppt
- PK
- Pre Formulation
- digoxina orina
- eoilson
- Bioinformatics-2009-Surovtsova-2816-23.pdf
- Hidrolisis de La Maltosa

You are on page 1of 42

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

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.

concentration in plasma is expressed by a bi exponential

equation 1.

Equation-1

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

>> 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

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 )

curve logCp

Cp

Time(hours)

Figure 2. Semi-log Plot of Cp versus Time after oral

administration of single dose

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

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 )

Residual curve

Cp

Slope=- ka/2.303

Time(hours)

Figure 3. Semi-log Plot of Cp versus Time

Slope= -kel/2.303

estimated..

can be

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

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.

Residual curve

Lag time t0

Time(hours)

The estimation of the rate constant for absorption and

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

COMPARTMENT MODEL

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

Log B

First residual curve

Second residual curve

Slope=-/2.303

Log C

Slope=-ka/2.303

Time(hours)

Figure 5

Slope=-/2.303

APPLICATIONS

To

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.

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

t

dA Vd dC K.Vd . C. dt

t

At A0 Vd Ct C0 K.Vd C. dt

0

t

At Vd . Ct KVd

. C. dt

0

At

Ct K . C. dt

Vd

0

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

divided by equation 10

t

Ct K C. dt

0

At / A

K Cdt

11

12

figure 7

Slope=absorption

rate constant

Time(hours)

Percent of unabsorbed

drug versus time plot-Zero

order

Percent of unabsorbed

figure 6

Slope=-ka/2.303

Time(hours)

Logarithm Percent of

unabsorbed drug versus

time plot-First order

1.

2.

3.

4.

5.

6.

7.

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

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

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

Setting the value of t = , this equation becomes

Ab /Vc = 0+ 0 + K13 [AUC]0

Ab /Vc = K13 [AUC]0

Equation 3.4

F = Ab /X0

Equation 3.5

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.

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 .

Using a plot of percent of drug unabsorbed versus time.

For a one-compartment model

Ab =DB+DE

5.1

5.2

constant k e

5.3

5.4

Assuming a one-compartment model,

Substituting V D C p into Equation 5.2

5.5

5.6

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.

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

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.

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.

2. Malcolm Rowland, Thomas N.Tozer, Clinical Pharmacokinetics,concepts and

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

9. www.medscape.com

10. www.pharmainfo.net

- Chapter 11-Homogeneous ReactionUploaded byBryan Manalili
- Chemistry and Differential EquationsUploaded byJeremy Lai
- Pharmacokinetic modelsUploaded byNeeraj Kumar
- Ladmer SystemUploaded byAbdul Mannan
- b001Validation and Evaluation of Linguistic LogicsUploaded bysfofoby
- b001Validation and Evaluation of Linguistic LogicsUploaded bysfofoby
- EMEA - Summary of the Product CharacteristicsUploaded bykadec
- Physical Chemistry Chapter 11 3 AtkinsUploaded bywen
- pHUploaded byAdrien Ofthestone
- lec25.pdfUploaded byRavi
- 0 - Introduction.pdfUploaded byDan Enzer
- Compartment ModelingUploaded byPinkishBlue
- Ece4343 Week 3 sUploaded byMohsen Mohammad
- DRUG INTERACTION bu'azizah.pptUploaded byFrans Apandi
- PKUploaded byMustafa Shahin
- Pre FormulationUploaded byCm Mouli
- digoxina orinaUploaded byXochitl C. Palomec
- eoilsonUploaded byHassan Funsho Akande
- Bioinformatics-2009-Surovtsova-2816-23.pdfUploaded byGokce Tuncer
- Hidrolisis de La MaltosaUploaded byToti Toti
- Development Polymeric Micellar Formulation Valspodar PK Rat_EuJPharmBiopharm_2010Uploaded bymelisabarron
- Biopharmaceutics Note 7th SemUploaded bymj.vinoth@gmail.com
- Accelerated TitrationUploaded bytamara_0021
- GLPUploaded byalien2019
- 1-s2.0-S0960894X06002290-main.pdfUploaded byebi1364
- Ekc471 NotesUploaded byArka Guha
- yr12_3u_t1_2005Uploaded byMoriNoAndo
- Exerc12 Zeh (1)Uploaded byJordana Colman
- 034120 Pharmacokinetics of Meropenem During Intermittent and Continuous Intravenous Application in Patients Treated by Continuous Renal Replacement TherapyUploaded byFranz Josef Tarigan
- Anti Tb DrugUploaded byardellatri

- Fake Book Pop RockUploaded byviolinslut
- SciSoc Academic Internships Event - 24th November 2018Uploaded byFilip Ilievski
- Lipid-based Transfection Reagents Exhibit Cryo-InducedUploaded byFilip Ilievski
- ijms-18-01291Uploaded byFilip Ilievski
- Led Zeppelin Stairway ArrUploaded byReversewk2000
- HVA VaccineUploaded byFilip Ilievski
- bi980300hUploaded byFilip Ilievski
- Old IzergilUploaded byAlexandra Dorobanţu
- Topic 9- SuppositoriesUploaded byFilip Ilievski
- Bacteria as gene carrier vectorsUploaded byFilip Ilievski
- 10.1038s41551-017-0137-2Uploaded byFilip Ilievski
- Maeda 2001Uploaded byFilip Ilievski
- Absorption WindowsUploaded byFilip Ilievski
- Art. Application of the Biopharmaceutical (1)Uploaded byDeisy Santodomingo
- Microsponges QbDUploaded byFilip Ilievski
- aspirinresistance-1Uploaded byFilip Ilievski
- ProjectARS PDF 449Uploaded byFilip Ilievski
- liposomesUploaded byFilip Ilievski
- Depo FoamUploaded byFilip Ilievski
- Encyclopedia of Pharmaceutical Technology, Third EditionUploaded byFilip Ilievski
- Magistri (Elektroliza) NovaUploaded byFilip Ilievski
- Predavanje 10 Novo (F-elementi)Uploaded byFilip Ilievski
- analiticka praktikumUploaded byFilip Ilievski
- BayesUploaded bySiddhesh Parab
- Cae Reading Part 1Uploaded bybudisupriyanto

- Emergency Drugs in General PracticeUploaded bykhubu88
- Drug AbuseUploaded byMichelle Agustin Nogoy
- FiberCon (polycarbophil)Uploaded byE
- Ppt EndometriosisUploaded byRanny
- The Manual of Empathogenic Etiquette and Safety.pdfUploaded byEMLonergan
- Investor Presentation [Company Update]Uploaded byShyam Sunder
- Administering Parenteral MedicationUploaded byggrrk7
- El Perfil Farmacocinético de Plasma y Cerebro Del Cannabidiol (CBD)Uploaded byKarmen Goretti Villa
- Prometric MCQs (Blank)Uploaded byjyothisahadevan
- Bab 22-23 Kaplan & Saddock Psychiatry Drug TreatmentUploaded byCindy Rara
- ICU Neuromuscular BlockadeUploaded bydamondouglas
- Overview Manajemen Dan Penggunaan Obat.pptx- Mm.pptx ShareUploaded byirma
- Mictonorm Product InsertUploaded byChung Wen Wei
- Dosis Oseltamivir CDCUploaded byivonne marin
- FLUOROQUINOLONE ANTIMICROBIALS IN ANIMAL HEALTHUploaded bySunil
- MigraineUploaded by928cb
- Journal for Chapter 9 Phar DoseUploaded byGrace Ann Zacarias
- Analgesic & AntipyreticsUploaded byRaymund Razon
- VademekumENG 2013.pdfUploaded byAmina Bećiragić
- Acute Pain for MS3Uploaded byAndrias Oz
- ichs3b.pdfUploaded bymaheshknm
- 21221112-Brand-Name-Diflucan-Generic-Name-Fluconazole-Drug-Classification-Antibiotics-Antifungal.docUploaded bycen janber cabrillos
- RA 9165 – An Act Instituting the Comprehensive Dangerous Drugs Act of 2002Uploaded byPacific Spectrum
- Biowaivers & BiosimilarsUploaded byomicspublishinggroup
- Antineoplastic sUploaded bysoban
- Omeperazole Dan LanzoperazoleUploaded byStefany Luke
- akurit 4 tbUploaded byNicollo
- Administration of Injections PresentationsUploaded bygopusankar
- STUDY OF PHARMACODYNAMIC INTERACTION BETWEEN DICLOFENAC AND RUMACCT®, A POLYHERBAL FORMULATION IN ALBINO RATSUploaded byRajesh Kumar
- LoperamideUploaded byRama Biomantara