DRUG ABSORPTION

Dr. Chandane R. D.
Asst Professor
Dept of Pharmacology
Govt Medical College,
Akola
 Pharmacokinetics, Overview

 Pharmacokinetics: the study of the movement of drugs in the body, including the processes of
absorption, distribution, localization in tissues, biotransformation and excretion
 Learning pharmacokinetics is of great practical importance in the choice and administration of
a particular drug for a particular patient, e.g., one with impaired renal function
INTRODUCTION TO ABSORPTION
 Passage of drug through cell membranes
to reach its site of action.
 Definition :
The process of movement of
unchanged drug from the site of
administration to systemic circulation.
 There always exist a correlation between the plasma
concentration of a drug & the therapeutic response & thus,
absorption can also be defined as the process of movement of
unchanged drug from the site of administration to the site of
measurement.
i.e., plasma.
Is the passage of drug through cell
membranes to reach its site of action.

Mechanisms of drug absorption

1. Simple diffusion = passive diffusion.

2. Filtration

3. Facilitated diffusion.

4. Active transport.

5. Pinocytosis (Endocytosis).
CELL MEMBRANE
 CELL MEMBRANE
 Also called the plasma membrane, plasmalemma or
phospholipid bilayer.
 The plasma membrane is a flexible yet sturdy barrier that
surrounds & contains the cytoplasm of a cell.

 Cell membrane mainly consists of:

1. Lipid bilayer-
-phospholipid
-Cholesterol
-Glycolipids.
2. Proitens-
-Transmembrane proteins
-Lipid anchored proteins-like G protein
-Peripheral Proteins

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 watersoluble drug (ionized or polar) is readily
absorbed via aqueous channels or pores in cell
membrane.

 Lipidsoluble drug (nonionized or non polar) is

readily absorbed via cell membrane itself.
Characters
 common.
 Occurs along concentration gradient. Non
selective
 Not saturable
 Requires no energy
 No carrier is needed
 Depends on lipid solubility.
 Depends
pka of drug - pH of medium.
Drugs exist in two forms ionized (water soluble &
nonionized forms (lipid soluble) in equilibrium.
Drug ionized + nonionized

Only nonionized form is absorbable.

Nonionized / ionized fraction is determined
by pH and pKa according to
Henderson-Hasselbach
pH=pKa+log Conc of ionized drug / Conc of unionized drug
PKa of the drug
(Dissociation or ionization constant):
pH at which half of the substance is ionized &
half is unionized.
pH of the medium
Affects ionization of drugs.
Weak acids  best absorbed in stomach.
Aspirin, Phenobarbitone, penicillin v
Weak bases  best absorbed in intestine.
Atropine, ephedrine, Chloroquine
2. PORE TRANSPORT/ FILTRATION
It involves the passage of ions through Aq. Pores (4-
40 A0)
Low molecular weight molecules (less than 100
Daltons) eg- urea, water, sugar are absorbed.
Also imp. In renal excretion, removal of drug from
CSF and entry
of drugs into liver.

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 Occurs along concentration gradient.
 Requires carriers
 Selective.
 Saturable.
 No energy is
required.
 Relatively unusual.
 Occurs against concentration gradient.

 Requires carrier and energy.

 Specific

 Saturable.

 Iron absorption.

 Uptake of levodopa by brain.

ACTIVE TRANSPORT
Primary Active transport- Energy derived directly by
hydrolysis of ATP. ATP binding cassettee (ABC)
transporter have ATPase activity at intracellular loop.
This mediate only efflux
Secondary Active transport- this is effected by
another set of SLC transporter, energy to pump one
solute is derived from downhill movement of another
solute. When conc gradient of both solute moves in
same direction ,it is called symport or cotransport but
when they moves in opposite direction, is termed as
antiport or exchange transport. This mediate both
uptake and efflux of drug.
Active transport Carrier-mediated
facilitated diffusion
Against concentration along concentration
gradient gradient
(From low to high) (From high to low)

Needs carriers Needs carriers

Selective, saturable Selective, saturable

Energy is required No energy is required

Passive transport Active transport

Along concentration against concentration

gradient gradient
(From high to low) (From low to high)
No carriers Needs carriers

Not selective Selective, saturable

Not saturable
No energy energy is required
 Mechanism Direction Energy required Carrier Saturable

Passive diffusion Along gradient No No No

Facilitated diffusion Along gradient No Yes Yes

Active transport Against gradient Yes Yes Yes
ENDOCYTOSIS
It involves engulfing
extracellular
materials within a
segment of the cell
membrane to form
a saccule or a
vesicle (hence also
called as
corpuscular or
vesicular transport)
which is then
pinched off
intracellularly. 21
 In endocytosis, there are three process:

A) Phagocytosis

B) Pinocytosis

C) Transcytosis- It is a phenomenon in which

endocytic vesicle is transferred from one
extracellular compartment to another.

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A) PHAGOCYTOSIS

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5. PINOCYTOSIS
Pinocytosis ("cell-drinking")

Uptake of fluid solute.

A form of endocytosis in which small particles are

brought into the cell in the form of small vesicles which
subsequently fuse with lysosomes to hydrolyze, or to
break down, the particles.

This process requires energy in the form of (ATP).

Polio vaccine and large protein molecules are absorbed

by pinocytosis

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B) PINOCYTOSIS

This process is
important in the
absorption of oil
soluble vitamins &
in the uptake of
nutrients.

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 Plasma level curve

 Cmax = maximal drug level obtained with the dose.

 tmax = time at which Cmax occurs.
 Lag time = time from administration to appearance in blood.
 Onset of activity = time from administration to blood level reaching minimal effective
concentration (MEC).
 Duration of action = time plasma concentration remains greater than MEC.
 Time to peak = time from administration to Cmax.
 1- Absorption
 It is the process of entry of drug from site of administration into systemic
circulation.

 Factors influencing absorption

 A- Factors related to drug
a) Physicochemical properties:
1-Degree of ionization: highly ionized drugs are poorly absorbed.
2-Degree of solubility: High lipid/water partition coefficient increases
absorption.
3-Chemical nature: inorganic iron is better absorbed than organic iron.
4-Valency: ferrous salts are more absorbed than ferric,
-so vitamin C increases absorption of iron.
b) Pharmaceutical form of drug:
Absorption of solutions is better than suspensions or tablets.
 1- Absorption, Factors Influencing Absorption, contd
 B- Factors related to the patient:
1-Route of administration:
absorption is faster from i.v. > inhaled > i.m. > oral > dermal administration

seconds minutes hours

2-Area and vascularity of absorbing surface:
absorption is directly proportional to both area and vascularity. Thus
absorption of the drug across the intestine is more efficient than across the
stomach, as intestine has more blood flow and much bigger surface area
than those of the stomach
3-State of absorbing surface: e.g. atrophic gastritis and mal-absorption
syndrome decrease rate of absorption of drugs.
4-Rate of general circulation: e.g., in shock, peripheral circulation is reduced
and I.V. route is used.
5-Specific factors and presence of other drugs: e.g. intrinsic factor of the
stomach is essential for vitamin B12 absorption from lower ileum and
adrenaline induces vasoconstriction so delay absorption of local anesthetics.
 PHYSIO-CHEMICAL FACTORS

 PHYSICAL FACTORS
 PHYSIO-CHEMICAL FACTORS

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 PHYSICAL FACTORS
1. PARTICLE SIZE
Smaller particle size, greater surface area then higher
will be dissolution rate, because dissolution is thought to
take place at the surface area of the solute( Drug).

This study is imp. for drugs that have low aqueous

solubility. Absorption of such drugs can be increased by
increasing particle size by Micronization.

 ex. Griseofulvin, active intravenously but not

effective when given orally.

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 1.PARTICLE SIZE

To poor soluble drug, disintegration agents and surface

active agents may be added .
• ex. Bioavailability of Phenacetin is increased by tween 80.

 Micronization also reduces the dose of some drugs

• ex. the dose of griseofulvin is reduced to one half while
the dose of spironolactone is reduced to one twentieth.

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 Lesser particle size is always not helpful

Ex. Micronization of Aspirin, phenobarbital, lesser

effective surface area and hence
lesser dissolution rate

Reasons:

On their surface, hydrophobic drugs absorb air and

reduce their wettability

 Particle having size below 0.1 micron reaggregate to

form large particle

 Particle having certain micro size get electrical charge

which preventing contact with wetting medium
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Finally drug size reduction and subsequent increase
in surface area and dissolution rate is always not
useful.

Ex. of such drugs are Penicillin G & Erythromycin

These Drugs are unstable and degrade quickly in
solution.

Sometime, reduction in particle size of nitrofurantoin

and piroxicam increase gastric irritation

These problem can be overcome by

Microencapsulation.

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 2. Crystal Form

Substance can exist either in a crystalline or amorphous

form. When substance exist in more than one crystalline
form, the different form are called polymorphs and the
phenomena as polymorphism .
Two types of Polymorphism
1) Enantiotropic polymorph ex. Sulfur
2) Monotropic polymorph ex. Glyceryl Stearates

Polymorphs have the same chemical structure but different

physical properties such as solubility, density, hardness etc.
ex. Chlormphenicol has a several crystal form, and when
given orally as a suspension, the drug concentration in the
body was found to be dependent on the percentage of β -
polymorph in the suspension. The form is more soluble and
better absorbed.
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 One of the several form of polymorphic forms is
more stable than other. Such a stable form having low
energy state and high melting point and least aqueous
solubility
The remaining polymorphs are called as
metastable forms which have high energy state, low
melting point and high aqueous solubilities.

About 40% of all organic compounds exhibit

polymorphism.

Some drug exists in amorphous form which have

no internal crystal structure. Such drugs have high energy
states than crystal form hence they have greater aqueous
solubility than crystalline form.
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Ex. Novobiocin, cortisone acetate.
 3. Solvates And Hydrates
Many drugs associate with solvent and forms solvates
Solvent is water then it is called as hydrate
eg. Anhydrous form of caffeine and theophylline dissolve more rapidly
than hydrous form of these drugs.
Solvate form of drugs with org. solvent may dissolve fast in water than
non solvated form. eg. Fluorocortisone

4. Complexation
This property can influence the effective drug concentration in gi fluids.
Complexation of drug and gi fluids may alter the rate and extent of
absorption

eg. Intestinal Mucin form complex with Streptomycin and Dihydro

Streptomycin.
In some cases, Poor water soluble drugs can be administered as water soluble
complexes. eg. Hydroquinone with Digoxin.

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 5.Adsorption
It is a physical and surface phenomena where the drug molecules are
held on the surface of some inert substances by vanderwall’s forces.

ex. Charcoal used as an antidote; When it is co-administered with

promazine, then it reduces the rate and extent of absorption
Cholestyramine reduces the absorption of warfarin.

6.Drug Stability And Hydrolysis In GIT

Drugs undergoes various reactions due to wide spectrum of ph and enzymatic
activity of GI fluid namely acid and enzymatic hydrolysis.

eg. T½ of Penicillin G= 1 min. at pH 1

T½ of Penicillin G= 9 min. at pH2
So it means Penicillin G is stable at less acidic pH
Erythromycin and its esters are unstable at gastric fluid (T½=Less than 2
min.)
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 7. Salts
 Na or K salts of weak acid dissolves rapidly than free acid.
ex. Na salts of Novobiocin shows improved bioavailability
 Certain salts also may have low solubility and dissolution rate.

ex. Al salts of weak acid and pamoate salt of weak base

8. Presence Of Surfactant
Use of wetting agent and Solubilizing agent improve the Dissolution rate &
absorption of drugs.
Ex. Tween 80 increase the rate & extent of absorption of Phenacetin.

9. Dissolution
Disintegration is the formation of dispersed granules from an intact solid
dosage form whereas the dissolution is the formation of solvated drug
molecules from the drug

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 SOLID DRUG

DISSOLUTION

DRUG AT ABSORPTION
SITE

ABSORPTION

DRUG IN SYSTEMIC
CIRCULATION

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NOYES AND WHITNEY’S EQUATION

dc/dt = KS(CS-C)
Where,
dc/dt = Rate constant, K = constant, S = surface area of the
dissolving solid, Cs=solubility of the drug in the solvent,
C=concentration of drug in the solvent at time t.

Constant K=D/h
Where, D is the diffusion coefficient of the dissolving material and h is
the thickness of the diffusion layer

Here, C will always negligible compared to Cs

So,
dc/dt=DSCs/h

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 P H Y S I C O C H E M I C A L FA C TO R S

1) pH PARTITION THEORY (Brodie) :

It explain drug absorption from GIT and its distribution
across biomembranes.

Drug(>100 daltons) transported by passive diffusion

depend upon:

 dissociation constant, pKa of the drug

 lipid solubility, K o/w
 pH at absorption site.

Most drugs are either weak acids or weak bases whose

degree of ionization is depend upon pH of biological fluid.
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For a drug to be absorbed, it should be unionized and the
unionized portion should be lipid soluble.

The fraction of drug remaining unionized is a function of

both Dissociation constant (pKa) and pH of solution.

The pH partition theory is based on following assumption:

 GIT acts as a lipoidal barrier to the transport of the drug

 The rate of absorption of drug is directly proportional to
its fraction of unionised drug
 Higher the lipophilicity of the unionised degree, better
the absorption.

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HENDERSON HASSELBATCH EQUATION
For acid,
pKa - pH = log[ Cu/Ci ]
For base,
pKa – pH = log[ Ci/Cu ]
Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will
have > 99%of unionized form so gets absorbed in
stomach

Weak base quinine (pKa=8.5) will have very negligible

unionization in gastric pH so negligible absorption

Several prodrugs have been developed which are lipid

soluble to overcome poor oral absorption of their parent
compounds.
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eg. Pivampicilin, the pivaloyloxy-methyl ester of
ampicilin is More lipid soluble than ampicilin.

Lipid solubility is provided to a drug by its partition

coefficient between An organic solvent and water or
an aq. Buffer (same pH of ab. Site)
E.g. Barbital has a p.c. of 0.7 its absorption is 12%
Phenobarbital ( p.c = 4.8 absorption=12%)
Secobarbital (p.c =50.7 absorption=40%)

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2)DRUG SOLUBILITY

The absorption of drug requires that molecule be in solution at

absorption site.

Dissolution, an important step, depends upon solubility of drug

substance.

pH solubility profile:

pH environment of GIT varies from Acidic in stomach to slightly Alkaline

in a small intestine.

soluble
1)Basic drug 1) Acidic medium( stomach)
2)Acidic drug 2) basic medium( intestestine)

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Improvement of solubility:

Addition of acidic or basic excipient

Ex: Solubility of Aspirin (weak acid) increased by
addition of basic excipient.

For formulation of CRD , buffering agents may be

added to slow or modify the release rate of a fast
dissolving drug.

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PHARMACEUTICAL FACTORS
MEANS Absorption rate depends on the dosage
Form which is administered, ingredients used, procedures
Used in formulation of dosage forms.

The availability of the drug for absorption from the

dosage forms is in order.

Solutions > Suspensions > capsules > Compressed

Tablets > Coated tablets.

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 BIOAVAILABILITY
 The term bioavailability is defined as the rate and extent of absorption of unchanged
drug from its dosage form.
 It is the fraction of drug that reaches systemic circulation in an unchanged form and
becomes available for biological effect following administration by any route. It is
100% after IV administration.
 It is calculated by comparison of the area under the plasma concentration time curve
(AUC) after IV dose of a drug with that observed when the same dose is given by
another route e.g. oral.
Area under the curve (AUC) oral x 100
Oral bioavailability =
Area under the curve (AUC) I.V.
 Oral bioavailability depends on amount
absorbed and amount metabolized before
reaching systemic circulation (first pass
metabolism)
 Bioequivalence:
 Bioequivalence occurs when two formulations of
the same compound have the same
bioavailability and the same rate of absorption
BIOAVAILABILITY
Destroyed Not Destroyed Destroyed
in gut absorbed by gut wall by liver
Dose
to
systemic
circulation
Factors Affecting Bioavailability:

 Molecular weight of drug.

 Drug Formulation (ease of dissolution).

(solution > suspension > capsule > tablet)

 Drug solubility of the drug

 Chemical instability in gastric pH

(Penicillin & insulin )
 First pass metabolism reduces bioavai
Factors Affecting Bioavailability (BAV):

 Blood flow to absorptive site

Greater blood flow increases bioavailability
Intestine has greater blood flow than stomach
 Surface area available for absorption.

Intestinal microvilli increases it

 Rate of gastric emptying

rapid gastric emptying fast transit to

intestine
 pH of gut
 Intestinal motility (Transit Time)
Diarrhea reduce absorption
 Drug interactions

 Food

slow gastric emptying

generally slow absorption
Tetracycline, aspirin, penicillin V