1

ABSORPTION OF DRUGS FROM

NON PER OS EXTRA VASCULAR
ROUTES
 Contents1,
2
 Introduction

 Definition

 Otherthan oral
routes

 Advantages

 Summary

 Conclusion

 References 2
 Introduction1
NON PER OS Means other than oral routes
which bypasses the GIT and reaches to systemic
circulation.
One of the major advantages of administering
drugs by non-invasive transmucosal (&
transdermal) routes such as nasal, buccal, rectal,
etc. is that greater systemic availability is
attainable.

3
1

4
NON PER OS ROUTES1,2

 BUCCAL/SUBLINGUAL
 RECTAL
 TOPICAL
 INTRAMASCULAR
 SUBCUTANIOUS
 PULMONARY
 INTRANASAL
 INTRAOCCULAR
 VAGINAL 5
 1. BUCCAL/SUBLINGUAL1,3

 Buccal Route : The medicament is placed between cheek and

the gum.(Glyceryl trinitrate)
 Sublingual Route : The drug is placed under the tongue and d
allowe
to dissolve.(Ergotamine)
 Advantages :-
a) Rapid absorption
b) No first-pass hepatic metabolism
c) No degradation of drugs
 Factors:-
a) Lipophilicity of drugs
b) Salivary secretion

c) PH of the saliva
d) Binding to oral mucosa 6
e) Thickness of oral
epithelium
 Examples of drugs administered by oral mucosal route

Anti anginals - Nitrites and nitrates

Antihypertensives - Nifidipine
Analgesics - Morphine
Bronchodilators – Fenoterol
Steroids – oestradiol
Peptides - Oxytocin

Newer Approach- Translingual delivery (Buccal spray);

especially for children. Eg. Nitroglycerin spray
BUCCAL/SUBLINGUAL SITE 2

7
 2. RECTAL1,2
 The rectal route of administration is still an
important route for Children & Old Patients.
 The drug may be administered as
solutions(microenemas) or suppositories.
 Advantage :-
Examples of drugs
a) Absorption is more rapid
which are taken by
b) Bypasses presystemic hepatic this route:
metabolism Aspirin
 Factors:- Paracetamol
1. Presence of faecal matter
Theophylline
Few Barbiturates
2. pH of rectal fluid ( Around 8)

3. Drug Irritability 8

4. Surface area
 3. TOPICAL1,2
 Skin is largest organ of the body. Skin is commonly
employed as a site of drugadministration for local as well as
systemic effect.
 Liquid dosage forms such as Liniments,Lotions,Sprays.
 Semisolids like Ointments,Creams,Pastes,Gels ,etc are
conventional drug forms for topical drug delivery
 Advantages:-
a) Protect drug from GI & from first pass metabolism
b) Increased patient compliance by reduced dosing frequency
c) Easy to terminate drug therapy by removing transdermal
patch
 Factors:-
a) Skin condition
b) Composition of topical vehicle
9
c) Application procedure
d) External/environmental factors
TOPICAL SITE1

10
 4. INJECTIONS1,2

 Intravenous(IV) Injection.
Drug is directly goes into blood stream
 Intramuscular(IM) Injection.
Absorption of drugs from I.M. sites is relatively rapid but much
slower than I.V. injection.

 Subcutaneous(SC) Injection.
Absorption is slower than I.M. site due to poor perfusion

11
INJECTIONS CONTINUED…..

 Factors :-

a) Vascularity of injection site (arm (Deltoid) >Thigh (Vastus

lateralis) >Buttock (Glutius maximus))

b) Lipid solubility & Ionisation of drug

c) Molecular size of the drug

d) Volume of injection/Drug concentration

e) PH, composition & viscosity of injection vehicle

(Phenytoin at pH 12, precipitate formation takes place-12
slow absorption)
6. PULMONARY1,2

All drugs intended for systemic effect can be

administered by inhalation since the large surface
area of the alveoli .

 Advantages:-
a) Rapid absorption just like exchange of gases
between the blood and the inspired air
b) Lipid-soluble drugs are rapidly absorbed by passive
diffusion
c) Polar drugs absorbed by pore 13
transport
 PULMONARY
Drugs are generally administered either as gases or aerosols
In case of aerosol systems the drug delivery to lungs largely
depends upon the particle size of aerosolised droplets.
Particle size >10 microns do not reach pulmonary tree
Particle size of 0.6 microns absorption is rapid but susceptible
for easy exhalation.
Particle sizes between 1-5 microns deposit within lower
respiratory tract.
 7. INTRANASAL1
The nasal route is becoming increasingly popular for systemic
delivery especially of some peptide and protein drugs

 Advantages:-
a) Rapid absorption due to rich vasculature and high permeability
b) Drugs from this route reaches the systemic circulation may
cross BBB
 FACTORS:-
a) Required high lipophilic drugs
b) Smaller molecular weight is required
c) pH of nasal secretion
d) Pathological condition 16
 8. INTRAOCCULAR2
Topical application of drugs to the eyes is mainly
meant for local effects such as mydriasis, miosis,
anaesthesia or treatment of infections,gloucoma,etc.
 Advantages:-

a) Lipophilic as well as Hydrophilic drugs are absorbed

b)pH of lachrymal fluid influenceabsorption of

electrolytes weak
 Factors:-

a) Rate of blinking shows loss of drug

b) Viscosity of drug also affect on absorption

17
 9. VAGINAL1,2
Drugs meant for intravaginal application are
ganerally intended to act locally in the
treatment of bacterial or fungal infection or
prevent conception
 Advantages:-
a) Easy administration

b) Controlled delivery & termination of drug

action when desired, with this route

18
SUMMARY OF MECHANISM AND DRUGS ABSORBED
FROM VARIOUS NON INVASIVE ROUTES1:-
ROUTES ABSORPTION DRUG DELIVERED
MECHANISM

1.Buccal/Sublingual Passive diffusion,carriar Nitrites,antianginal,mo

mediated transport rphine,etc.

2.Rectal Passive diffusion Aspirin,Paracetamol,ba

rbiturates,etc.
3.Transdermal Passive diffusion Nitroglycerine,lidocaine
,etc.
4.Intramuscular Passive diffusion, Phenytoin, digitoxine
endocytosis,pore
transport
5.Subcutaneous Passive diffusion Insuline, heparin,etc.

6.Inhalation Passive diffusion,Pore Salbutamol, cromolyn

transport 19
ROUTES ABSORPTION DRUG DELIVERED
MECHANISM

7.Intranasal Passive diffusion, Phenylpropanolamine,

Pore transport antihistaminics

8.Intraocular Passive diffusion Atropine,pilocarpine

9.Vaginal Passive diffusion Steroidal drugs &

contraceptives

20
 CONCLUSION1,2
 Absorption of drug is rapid
 Directly reaches the systemic circulation

 Avoid the GI degradation and/or hepatic

metabolism
 Easy to administered

 Shows the more bioavailability than oral

route

21
REFERANCES

1. Brahmankar D. M., Jaiswal S.B.,

Biopharmaceutics & Pharmacokinetics A
Treatise, Second Edition 2009 Published by Jain
M.K. for Vallabh Prakashan, Delhi.81-92.
2. Kulkarni J.S., Pawar A.P., Shedbalkar V.P.,
Biopharmaceutics & Pharmacokinetics First
edition 2006, CBS Publication,New Delhi.47- 59.
3. www.vodlo.com

22
THANK
YOU 23
DISSOLUTION & IVIVC
 BIOAVAILABILITY
ENHANCEMENT TECHNIQUES

Dr.M.Ravindra Babu M.Pharm., PhD.,

Associate Professor
• DEFINITION : Solubility is defined in quantitative
terms as concentration of solute in concentrated
solution at a certain temperature, and in qualitative way
it can be defined as a spontaneous interaction of two or
more substances to form a homogenous molecular
dispersion.

• Solubilization can be defined as a preparation of

thermodynamically stable isotropic solution of a
substance normally insoluble or slightly soluble in a
given solvent by introduction of an additional
component or components.
The biopharmaceutical classification system (BCS)

CLASS SOLUBILITY PERMEABILITY ABSORPTION RATE LIMITING

PATTERN STEP IN
ABSORPTION

I High High Well absorb Gastric

emptying

II Low High variable Dissolution

III High Low Variable Permeabilit

y

IV Low Low Poorly Case by

absorb case
The pharmacopoeia lists solubility in terms of number of
milliliters of solvent required to dissolve 1g of solute. The
Indian pharmacopoeia provides general terms to describe
a given range. These descriptive terms are given as:
DEFINITION PARTS OF SOLVENT
REQUIRED
FOR 1 PART OF SOLUTE
Very soluble <1
Freely soluble 1 - 10
Soluble 10 – 30

Sparingly soluble 30 - 100

Slightly soluble 100 - 1000

Very slightly soluble 1000 – 10,000

Insoluble >10,000 6
• Therapeutic effectiveness of a drug depends upon the
bioavailability and ultimately upon the solubility of drug
molecules.
• Solubility is one of the important parameter to achieve
desired concentration of drug in systemic circulation for
pharmacological response to be shown.
• Currently only 8% of new drug candidates have both high
solubility and permeability.
• Nearly 40% of the new chemical entities currently being
discovered are poorly water soluble.
• More than one-third of the drugs listed in the U.S.
Pharmacopoeia
fall into the poorly water-soluble or water-insoluble categories.
• Low aqueous solubility is the major problem encountered
with formulation development of new chemical entities.
• Any drug to be absorbed must be present in the form of an
The process of solubilization involves the breaking of inter-
ionic or intermolecular bonds in the solute, the separation of
the molecules of the solvent to provide space in the solvent
for the solute, interaction between the solvent and the solute
molecule or ion.
II. Chemical Modifications
1. Change in the pH
2. Use of buffer
3. Derivatization

III. Other methods

1. co-crystallisation
2.co-solvency 3.Hydrotrophy 4.Solubilizing
agents
5.Selective adsorption on insoluble carrier 6.
Solvent deposition
7.Using soluble prodrug 8.Functional polymer
technology 9.Precipitation Porous 10.
microparticle technology 11.Nanotechnology
approaches
3.Sonocrystallisation :
Particle size reduction on the basis of crystallisation
by using ultrasound is Sonocrystallisation .
Sonocrystallisation utilizes ultrasound power for inducing
crystallisation . It not only enhances the nucleation rate but
also an effective means of size reduction and controlling
size distribution of the active pharmaceutical ingredients.
Most applications use ultrasound in the range 20 kHz- 5
MHz.
4. Supercritical fluid process :
• A supercritical fluids are dense non-condensable fluid whose
temperature and pressure are greater than its critical temperature (
Tc ) and critical pressure ( Tp ) allowing it to assume the properties of
both a liquid and a gas.
• Through manipulation of the pressure of SCFs, the favourable
characteristics of gases – high diffusivity, low viscosity and low
surface tension may be imparted upon the liquids to precisely control
• Once the drug particles are solubilised within SCFs, they
may be recrystalised at greatly reduced particle sizes.
• A SCF process allows micronisation of drug particles
within narrow range of particle size, often to sub-micron
levels.
B. Modification of the crystal habit:

Polymorphs

Enantiotropic Monotropic
One polymorphs form can No reversible
change reversibly into another transition is possible.
at a definite transition
temperature below the melting
point.
• Metastable forms are associated with higher energy and
thus higher solubility. Similarly the amorphous form of drug
is always more suited than crystalline form due to higher
energy associated and increased surface area.
• The anhydrous form of a drug has greater solubility than the
hydrates. This is because the hydrates are already in
interaction
 with water and therefore have less energy for crystal
breakup in comparison to the anhydrates.
• They have greater aqueous solubility than the crystalline
forms because they require less energy to transfer a
molecule into solvent. Thus, the order for dissolution of
different solid forms of drug is
Amorphous > metastable polymorph > stable
polymorph
• Melting followed by a rapid cooling or recrystallization
from different solvents can produce metastable forms of
a drug.
The surface of the cyclodextrin molecules makes them water
soluble, but the hydrophobic cavity provides a
microenvironment for appropriately sized non-polar
molecules. Based on the structure and properties of drug
molecule it can form 1:1 or 1:2 drug cyclodextrin complex.
Three naturally occurring CDs are α Cyclodextrin, β
Cyclodextrin, and γ Cyclodextrin.
 E. Solubilization by
surfactants: Surfactants are
molecules with distinct polar
Most surfactants consist of
and nonpolar a hydrocarbon segment
regions.
connected to a polar group. The polar group can be anionic,
cationic, zwitter ionic or nonionic. The presence of
surfactants
may lower thesurface tension and increase the solubility of
the drug within an organic solvent .
Microemulsion : A microemulsion is a four-component system
composed of external phase, internal phase, surfactant and co
surfactant . The addition of surfactant, which is predominately
soluble in the internal phase unlike the co surfactant , results
in the formation of an optically clear, isotropic,
thermodynamically stable emulsion. It is termed as
microemulsion because of the internal phase is <0.1 micron
droplet diameter.
26
 The surfactant and the co surfactant alternate each other
and form a mixed film at the interface, which contributes to
the stability of the microemulsion .
Non-ionic surfactants, such as Tweens ( polysorbates ) and
Labrafil ( polyoxyethylated oleic glycerides ), with high
hyrophile-lipophile balances are often used to ensure
immediate formation of oil-in- water droplets during
production.
Advantages :
 Ease of preparation due to spontaneous formation.
 Thermodynamic stability,
transparent and elegant appearance,
enhanced penetration through the biological membranes,
increased bioavailability and
less inter- and intra-individual variability in drug
pharmacokinetics.
III. OTHER METHODS.

1.Co-crystallization:
A co-crystal may be defined as a crystalline
material that consists of two or more molecular species
held together by non-covalent forces.
•Co-crystals are more stable, particularly as the co-
crystallizing agents are solids at room temperature.
•Co-crystals can be prepared by evaporation of a heteromeric
solution or by grinding the components together.
•Another technique for the preparation of co-crystals
includes sublimation, growth from the melt, and slurry
preparation.
•Only three of the co-crystallizing agents are classified as
generally recognised as safe (GRAS) it includes saccharin,
nicotinamide and acetic acid limiting the pharmaceutical
applications.
 3. Hydrotrophy : Hydrotrophy designate the increase in
solubility in water due to the presence of large amount of
additives. The mechanism by which it improves solubility is
more closely related to complexation involving a weak
interaction between the hydrotrophic agents (sodium
benzoate, sodium acetate, sodium alginate, and urea).
4. Solubilizing agents: The solubility of poorly soluble drug
can also be improved by various solubilizing materials. PEG
400 is improving the solubility of hydrochlorthiazide85.
Modified gum karaya (MGK), a recently developed excipient
was evaluated as carrier for dissolution enhancement of
poorly soluble drug, nimodipine .

5. Selective adsorption on insoluble carriers: A highly active

adsorbent such as inorganic clays like Bentonite can
enhance the dissolution rate of poorly water-soluble drugs
such as griseofulvin, indomethacin and prednisone by
maintaining the concentration gradient at its maximum. 2
reasons suggested for rapid release of drugs from the
surface of clays :-
1. weak physical bonding between adsorbate and
adsorbent.
2. hydration and swelling of the clay in the aqueous media.
11. Nanotechnology approaches : For many new chemical
entities of very low solubility ,oral bioavailability
enhancement by micronization is not sufficient because
micronized product has a tendency of agglomeration, which
leads to decreased effective surface area for dissolution .
Nanotechnology refers broadly to the study and use of
materials and structures at the nanoscale level of
approximately 100 nanometers (nm) or less .

NANOCRYSTAL: Size: 1-1000 nm Crystalline material with

dimensions measured in nanometers. There are two distinct
methods used for producing nanocrystals . 1 . bottom-up. 2.
top- down . The top-down methods (i.e. Milling and High
pressure homogenization ) start milling down from
macroscopic level, e.g. from a powder that is micron sized.
In bottom-up methods (i.e. Precipitation and Cryo -vacuum
method), nanoscale materials are chemically composed
from atomic and molecular components.
NanoMorph :
•The NanoMorph technology is to convert drug substances
with low water-solubility from a coarse crystalline state into
amorphous nanoparticles .
•A suspension of drug substance in solvent is fed into a
chamber, where it is rapidly mixed with another solvent.
Immediately the drug substance suspension is converted
into a true molecular solution. The admixture of an aqueous
solution of a polymer induces precipitation of the drug
substance. The polymer keeps the drug substance particles
in their nanoparticulate state and prevents them from
aggregation or growth. Using this technology the coarse
crystalline drug substances are transformed into a
nanodispersed amorphous state, without any physical milling
or grinding procedures. It leads to the preparation of
amorphous nanoparticles
.
 Bioavailability
Drug Product &
Bioequivalence
Drug in Distribution to
Blood Tissue and Receptor sites

Excretion Metabolism

1
 CONTENTS
 Definitions
 Objectives of Bioavailability studies
 Methods of Bioavailability measurement
--Pharmacokinetic methods:
1. Plasma level time studies
2. Urinary excretion studies
--Pharmacodynamic methods:
1. Acute pharmacological response
2. Therapeutic response
 In vitro dissolution studies and bioavailability
 IVIVC Correlation
 Bioequivalence experimental study designs
1. Completely randomized designs
2. Randomized block designs
3. Repeated measures, cross over, carry-over designs
4. Latin square designs
 Statistical interpretation of bioequivalence data
1.Analysis of variance (ANOVA)
2.Confidence interval approach 2
 Definitions
Bioavailability:
It is rate and extent of absorption of unchanged drug from its
dosage form.
Rate- acute conditions- asthma, pain etc
Extent( amount ) – chronic conditions- hypertension.
Influence of route of administration
PARENTRAL> ORAL> RECTAL>TOPICAL

Absolute bioavailability:
When systemic availability of a drug administered orally
is determined in comparison to its I.V. administration,
denoted by F.

Relative bioavailability:
When systemic availability of a drug after oral administration
is
Compared with that of oral standard of the same drug 3
( Solution or suspension )and denoted by Fr.
Chemical equivalence:
When two or more drug products contain the same chemical
substance as an active ingredient in the same amount it is
called chemical equivalence.

Bioequivalence:
It is relative term that denotes drug substance in two or more
identical dosage forms reaches the systemic circulation at the
same relative rate to the same relative extent.

i.e. plasma concentration-time profiles will be identical without

significant statistical differences.

4
 Objectives of Bioavailability studies

It is important in the
Primary stages of development of dosage form of new drug
entity to find its therapeutic utility.

Determination of influence of excipients on absorption.

Development of new formulations of existing drugs.

 Control of quality of drug products and influence of

processing factors , storage and stability on absorption.

 Comparison of drug in different dosage forms or same

dosage form of different manufacturer.
5
Single dose versus multiple dose studies:
Single dose bioavailability studies are very common, easy, less exposure to
drugs,
less tedious. However it is difficult to predict the steady state
characteristics
and inter subject variability with these studies.
Advantages of multiple dose study:
-Accurately reflects manner in which drug will be used
clinically.
-Requires collection of few blood samples.
-Drug levels are higher due to cumulative effect and
useful for less sensitive analytical methods
-Better evaluation of controlled released formulation.
-Nonlinearity if present , can be easily determined.
-No need of long wash out periods.
Healthy subjects versus Patients:
Generally bioavailability study should be carried out in patients, as patient
get
benefited from the study, reflects better therapeutic efficacy, drug
absorption
pattern in disease state can be studied, avoids ethical quandary of 6
administering
 Methods of Bioavailability measurement
Pharmacokinetic methods
1. Plasma level time studies:
most reliable method of choice comparison to urine data method
Single dose: serial blood samples collection – 2-3 half lifes
Plot concentration vs time
For I.V. Sampling started within 5 min and subsequent samples at 15 min
intervals
For oral dose at least 3 points taken on absorption curve ( ascending part)
Parameters considered important in plasma level time studies
1. Cmax : It is peak plasma concentration. It increases with dose as well as
increase in rate of absorption.
2. Tmax: The peak time at which Cmax atended.
3. AUC: Area under curve explains about amount of AUC drug. oral Dose int ravenous
F  
AUC int ravenous Dose oral
AUC TEST Dose
F rel   STD

AUC STD
Dose TEST

CSS MAX Dose  t test

F rel   STD

CSS MAX Dose TEST

 t7std
2. Urinary excretion studies:
This method is based on the principle that the urinary excretion of unchanged
drug is directly proportional to the plasma concentration of drug.
It can be performed if
-At least 20% of administered dose is excreted unchanged in urine.
The study is useful for
- Drugs that extensively excreted unchanged in urine eg. Thiazide diuetics
- Drugs that have urine as site of action eg. Urinary antiseptics like
nitrofurontoin.
Steps involved:
-collection of urine at regular intervals for 7 half lifes.
- Analysis of unchanged drug in collected sample.
- Determination of amount of drug at each interval and cumulative as well.
Criteria's must be followed
- At each sample collection total emptying of bladder is necessary.
- Frequent sampling is essential in the beginning to compute correct rate of
absorption.
- The fraction excreted unchanged in urine must remain constant.
Parameters considered important in Urinary excretion studies
1. (Dx/dt)max: Maximun urinary excretion rate
2. (tu)max: Time for maximum excretion rate 8
3. Xu∞: Cumulative amount of drug excreted in the urine.
 Pharmacodynamic
1. Acute pharmacological response:
methods
When bioavailability measurement by pharmacokinetic methods is difficult,
inaccurate or non reproducible this method is used. Such as ECG, EEG,
Pupil diameter etc.
It can be determined by dose response graphs. Responses measure for at
least 3 half lifes.
Disadvantages:
- Pharmacological response is variable and accurate correlation drug and
formulation is difficult.
-Observed response may be due to active metabolite.
2. Therapeutic response:
This method is based on observing clinical response in patients.
Drawbacks:
- Quantitation of observed response is too improper.
-The physiological status of subject assumed that does not change
significantly over duration of study.
-If multiple dose protocols are not involved. Patient receive only single dose
for few days or a week
-The patient s receiving more than one drug treatment may be compromised
9
due to drug-drug interaction.
In vitro dissolution studies and bioavailability:
The physicochemical property of most drugs that has greatest influence on
absorption from GIT is dissolution rate. However in vitro dissolution is good
substitute for in vivo study in terms of saving cost and time. The best
available tool today which can at least quantitatively assure about the
bioavailability of drug from its formulation is in vitro dissolution test.
In vitro- in vivo correlation ( IVIVC):
It is defined as the predictive mathematical model that describes the
relationship between in vitro property ( rate & extent of dissolution) and in
vivo response ( plasma drug concentration).
The main objective of developing and evaluating IVIVC is to use dissolution
test to serve as alternate for in vivo study in human beings.
IVIVC Levels:
Level A: The highest category of correlation. It represents point to point
correlation between in vitro dissolution and in vivo rate of absorption.
Advantages: serves as alternate for in vivo study, change in manf. Procedure
or
formula can be justified without human studies.
Level B: The mean in vitro dissolution time is compare with mean in vivo
residence time. It is not point to point correlation . Data can be used for
quality control standards. 10
Level C: It is single point correlation. e.g. t Tmax, Cmax. This level is only
 Types of bioequivalence studies
In vivo bioequivalence studies: when needed,
1. Oral immediate release product with systemic action
-Indicated for serious conditions requiring assured response.
-Narrow therapeutic window.
- complicated pharmacokinetic, absorption <70%, presystemic
elimination>70%, nonlinear kinetics.
2. Non-oral immediate release products
3. Modified release products with systemic action.
In vitro bioequivalence studies: If none of the above criteria is applicable
comparative in vitro dissolution studies can be done.
Biowaivers: In vivo studies can be exempted under certain conditions.
1. Drug product only differ in strength of drug provided,
- Their pharmacokinetics are linear, Drug & excipient ratio is same,
- both products manufactured by same manuf. at same site.
- BA/BE study done for original product, disso. rate same under same
conditions.
2. The method of production slightly modified in a way that not affect
bioavailability
3. The drug product meet following requirements: The product is in solubilised
11
 Bioequivalence experimental study designs
1.Completely randomized designs:
All treatments are randomly allocated among all experimental subjects.
e.g. If there are 20 subjects, number the from 1 to 20. randomly select non
repeating numbers among these labels for the first treatment. And then repeat
for all other treatments .
Advantages: Easy to construct, can accommodate any number of treatment
and subjects, Simple to analyze.
Disadvantages:
Although can be used for number of treatments, but suited for few treatments.
All subjects must be homogenous or random error will occur.
2.Randomized block designs:
First subjects are sorted in homogenous groups, called blocks and then
treatments are assigned at random within blocks.
Advantages:
Systematic grouping gives more precise results.
No need o equal sample size, any number of treatments can be followed,
statistical analysis is simple, block can be dropped , variability can be
introduced.
Disadvantages:
Missing observations in a block require more complex analysis. 12
3.Repeated measures, cross over designs:
It is a kind of randomized block design where same subject serves as a block.
Same subject utilized repeatedly so called as repeated measure design.
The administration of two or more treatments one after the other in a
specified or
random order to the same group of patients is called cross-over designs.
Advantages:
Good precision, Economic, can be performed with few subjects, useful in
observing
effects of treatment over time in the same subject.
Disadvantages:
Order effect due to position in treatment order.
Cary over effect due to preceding treatment.
Wash out period necessary – 10 elimination half lifes.
4.Latin square designs: All other above designs are continuous trial.
However in
Latin square design each subject receives each treatment during the
experiment.
It is a two factor design ( Rows=Subjects and Columns=Treatments ). Carry
–over
effects are balanced. 13
Advantages: minimize variability of plasma profiles and carry-over effects.
 Statistical interpretation of bioequivalence data
After the data has been collected , statistical methods must be applied to
determine
the level of significance or any observed difference in rate and /or extent of
absorption
to establish bioequivalence between two or more drug products.
1. Analysis of varience ( ANOVA): It is statistical procedure use to test data
for differences within and between treatment and control groups. A
statistical difference between the pharmacokinetic parameters obtained
from two or more drug products is considered statistically significant if
there is probability of less than 1 in 20 or 0.05 (p≤0.05) . The value of p
indicates the level of statistical significance.
2. Confidence interval approach: It is also called as two one-sided procedure
and used to demonstrate if bioavailability of test product is too low or too
high in comparison to reference product. 90% confidence interval of two
drug products must be within ±20% for bioavailability parameters such14as
 References
 Biopharmaceutics and pharmacokinetics – A Treatise ,
D. M. Brahmankar, Sunil B.Jaiswal. Vallabh prakashan
IInd
edition, pp- 315-366.
 Basics of Pharmaokinetics, Leon Shargel, fifth edition,
willey
publications, pp- 453-490.
 Internet sources.

15
16
 NON LINEAR
PHARMACOKINETICS
By
Dr.M.Ravindra Babu
Associate Professor
In most cases, at therapeutic doses, the change
in the amount of drug i the body or the
change in its plasma concentration due to
absorption, distribution, binding, metabolism
or excretion, is proportional to its dos
whether administered as a single dose or as
multiple doses. In such situations, the rate
processes are said to follow first-order or line
kinetics and all semilog plots of C versus t for
different doses, when corrected for dose
administered, are superimposable.
This is called principle of superposition.
The important pharmacokinetic paramete viz F.
Ka, KE Vd, ClR and ClH which describe the
time-course of drug in the body remain
unaffected by the dose i.e. the
pharmacokinetics are dose- independent. In
some instances, the rate process of a drug's
ADME are depends upon carrier or enzymes
that are substrate-specific, have definite
capacties, and susceptible to saturation at
high drug concentration. In such cases, an
essentially first-order kinetics transform into a
mixture of firs order and zero-order rate
processes and the pharmacokinetic
parameters change with the size of the
administered dose.
The pharmacokinetics such drugs are said
to be dose-dependent. Other terms
synonymous with it are mixed-order,
nonlinear and capacity-limited kinetics.
Drug exhibiting such a kinetic profile are
sources of variability in pharmacological
response.
There are several tests to detect nonlinearity in
pharmacokinetics
1. Determination of steady-state plasma concentration
at different doses. If the steady-state concentrations
are directly proportional to the dose, then linearity in
the kinetics exists. Such proportionality is not
observable when there is nonlinearity.
2. Determination of some of the important
pharmacokinetic parameters such as fraction
bioavailable, elimination half-life or tot systemic
clearance at different doses of the drug. Any change
 CAUSES OF NON LINEARITY
Nonlinearities can occur in drug absorption,
distribution, metabolism and excretion
Absorption:
Nonlinearity in drug absorption can arise
from 3 important sources
1. When absorption is solubility or dissolution
rate-limited e.g. griseofulvin. At higher
doses, a saturated solution of the drug is
formed in the GIT or at any other
extravascular site and the rate of
absorption attains a constant value.
2. When absorption involves carrier-mediated
transport systems c.g. absorption of
riboflavin, ascorbic acid, cyanocobalamin,
etc. Saturation of the transport system at
higher doses of these vitamins results in
nonlinearity.
3. When presystemic gut wall or hepatic
metabolism attains saturation e.g.
propranolol, hydralazine and verapamil.
Saturation of presystemic metabolism of
these drugs at high doses leads to
increased bioavailability.
The parameters affected will be F. Ka, Cmax
and AUC. A decrease in these parameters
is observed in the former two cases and
an increase in the latter case. Other
causes of nonlinearity in drug absorption
are changes in gastric emptying and GI
blood flow and other physiological factors.
Nonlinearity in drug absorption is of little
consequence unless availability is
drastically affected.
 DISTRIBUTION
Nonlinearity in distribution of drugs
administered at high doses may be due to
1. Saturation of binding sites on plasma
proteins e.g. phenylbutazone and
naproxen. There is a finite number of
binding sites for a particular drug on
plasma proteins and, theoretically, as the
concentration is raised, so too is the
fraction unbound.
2. Saturation of tissue binding sites e.g.
thiopental and fentanyl. With large single
bolus doses or multiple dosing, saturation
of tissue storage sites can occur.
In both cases, the free plasma drug
concentration increases but Vd increases
only in the former case whereas it
decreases in the latter.
Clearance is also altered depending upon
the extraction ratio of the drug. Clearance
of a drug with high ER is greatly increased
due to saturation of binding sites.
Unbound clearance of drugs with low ER
is unaffected and one can expect an
increase in pharmacological response.
 DRUG METABOLISM
Two important causes of nonlinearity in
metabolism are
1. Capacity-limited metabolism due to
enzyme and/or cofactor saturation.
Typical examples include phenytoin,
alcohol, theophylline, etc.
2. Enzyme induction e.g. carbamazepine,
where a decrease in peak plasma
concentration has been observed on
repetitive administration over a period of
time. Autoinduction characterized in this
case is also dose-dependent. Thus,
enzyme induction is a common cause of
both dose- and time-dependent kinetics.
 DRUG EXCRETION
The two active processes in renal excretion
of a drug that are
1. Active tubular secretion e.g. penicillin G.
After saturation of the carrier-system, a
decrease in renal clearance occurs.
 
2. Active tubular reabsorption e.g. water-
soluble vitamins and glucose. After
saturation of the carrier-system, an
increase in renal clearance occurs.
Other sources of nonlinearity in renal
excretion include forced diuresis, changes
in urine pH, nephrotoxicity and saturation
of binding sites. Biliary secretion, which is
also an active process, is also subject to
saturation e.g. tetracycline and
indomethacin.
 MICHAELIS MENTEN EQUATION

 The kinetics of capacity-limited or saturable

processes is best described by Michaelis-
Menten equation.
-dc/dt = Vmax C/Km+C
where,
-dC/dt = rate of decline of drug concentration
with time,
Vmax = theoretical maximum rate of the
process,
and Km = Michaelis constant.
 Three situations can now be considered
depending upon the values of Km and C
1. When Km=C:
Under this situation, the equation reduces to,
-dc/dt = Vmax/2
The rate of process is equal to one half its maximum rate.
2. When Km>>C:
Here, Km + C=Km and equation will become
-dc/dt = VmaxC/Km

The above equation is identical to the one that

describes first order elimination of a drug where
V max/km = K. This means that the drug
concentration in the body that results from usual
dosage regimens of most drugs is well below
the Km of the elimination process with certain
exceptions such as phenytoin and alcohol
3. When Km<<C:
Under this condition Km+C=C and the
equation will become
-dc/dt=V max
The above equation describes zero order
process