ABSORPTION OF

DRUGS

SUBMITTED BY

JASEEM.K

1ST YEAR M-PHARM

TOPICS

 DEFINITION

 STRUCTURE OF GIT

 MECHANISM OF TRANSPORT

 FACTORS AFFECTING ABSORPTION

 -PHYSIO-CHEMICAL FACTORS
DEFINITION

 It is defined as the process of movement of

unchanged drug from the site of
administration to the systemic circulation.
 There always present a correlation between
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.
STRUCTURE OF CELL
MEMBRANE
M ECHANISM OF DRUG
ABSORPTION

1. Passive diffusion
2. Carrier- mediated transport:
a) .Active diffusion
b). Facilitated diffusion
3. Pore Transport
4. Ionic or Electrochemical diffusion
5. Ion-pair transport
6. Endocytosis
PASSIVE D IFFUSION

Characters
 common.
 Occurs along concentration
gradient. Non selective
 Not saturable
 Requires no energy
 No carrier is needed
 Depends on lipid solubility.
 Depends on pka of drug - pH of
medium.
Expressed by Fick’s first law of diffusion -
“The drug molecules diffuse from a region of
higher concentration to one of lower
concentration until equilibrium is attained & the
rate of diffusion is directly proportional to the
concentration gradient across the membrane”.

dq/dt = D A Ko/w (Cgit – Cplm)/Vh

Sink condition

dQ/dt =P CGIT
Active Absorption

 Relatively unusual.
 Occurs against concentration
gradient.
 Requires carrier and energy.
 Specific
 Saturable.
 Iron ,K , Na , Ca
 Uptake of levodopa by brain.
PASSIVE AND ACTIVE TRANSPORT
FACILITATAED DIFFUSION

 Occurs along the concentration gradient

 Require carriers

 Saturable

 Stucture specific

 No energy required

 Mixed order kinetics

 monosaccharides , amino acids , vitamins

P ORE T RANSPORT

 Also known as convective transport, bulk flow

or filtration.

 Important in the absorption of low mol. Wt.

(less than 100). Low molecular size (smaller
than the diameter of the pore) & generally
water-soluble drugs e.g. urea, water & sugars

 The driving force for the passage of the drugs

is the hydrostatic or the osmotic pressure
difference across the membrane.
Rate of absorption via pore Transport depends on
the number & size of the pores, & given as follows:

dc = N. R2. A . ∆C
dt (η) (h)
where,
dc = rate of the absorption.
dt
N = number of pores
R = radius of pores
∆C = concentration gradient
η = viscosity of fluid in the pores
I ONIC OR E LECTROCHEMICAL
DIFFUSION

 Charge on membrane influences the

permeation of drugs.

 Molecular forms of solutes are unaffected by

the membrane charge & permeate faster
than ionic forms.

 The permeation of anions & cations is also

influenced by pH.
 Once inside the membrane, the cations are
attached to negatively charged intracellular
membrane, thus giving rise to an electrical
gradient.
 If the same drug is moving from a higher to
lower concentration, i.e., moving down the
electrical gradient , the phenomenon is
known as electrochemical diffusion
 Thus, at a given pH, the rate of
permeation may be as follows:
Unionized molecule > anions >
cations
I ON PAIR TRANSPORT

 It is another mechanism to explain the absorption

of such drugs which ionize at all pH condition.

 Quaternary ammonium compounds, sulfonic acid

 Although they have low o/w partition coefficient

values, they will penetrate the membrane by
forming reversible neutral complexes with
endogenous ions. e.g. mucin of GIT.

Such neutral complexes have both the required

lipophilicity as well as aqueous solubility for passive
diffusion.

This phenomenon is known as ion-pair transport.

E NDOCYTOSIS

 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

 Fats , starch , oil soluble vitamins

 Insulin

 Absorbed into lymphatic circulation –

bypassing first pass hepatic metabolism
In endocytosis, there are two process

A) Phagocytosis

B) Pinocytosis
P INOCYTOSIS

 This process is important in the absorption of oil

soluble vitamins & in the uptake of nutrients.
 FACTORS AFFECTING DRUG ABSORPTION

• PHYSIOLOGICAL FACTOR
PATIENT RELATED
FACTORS
• CLINICAL FACTOR

•Physico-chemical factors
PHARMACEUTICAL
FACTORS
•Formulation factors
P HYSICO - CHEMICAL FACTORS

 Drug solubility and dissolution rate.

 Particle size & effective surface area.
 Polymorphism & amorphism.
 Pseudopolymorphism
 Salt form of the drug
 Lipophilicity of the drug
 pKa of the drug & Ph
 Drug stability
D RUG SOLUBILITY &
D ISSOLUTION RATE

 Rate determining process in the absorption of

orally administered drugs are :-

1.rate of dissolution

2.rate of drug permeation through the

biomembrane

Hydrophobic-RDS- Dissolution

Eg:- griseofulvin , spiranolactone

Hydrophilic-RDS-permeation rate limited

Eg: - cromolyn sodium or neomycin

P ARTICLE SIZE & EFFECTIVE
SURFACE AREA

 Particle s size and surface area of a solid drugs are

inversely related to each other

 Smaller particle size-> greater surface area->rapid

dissolution

 Micronization –grater surface area-rapid

dissolution

hydrophilic drugs-follows

 Eg:-griseofulvin, spiranolactone
 Hydrophobic drugs-micronization-decrease
in effective surface area-fall in dissolution
rate
 Causes
 Adsorption of air to surafce
 Particle reaggregation
 Surface charge
 Eg:- aspirin , phenacetin
 In that case add-surfactants –tween 80

 hydrophilic diluents-PEG ,PVP

 DEXTROSE
D) POLYMORPHISM AND AMORPHISM
POLYMORPHISM

When substance exists in

different crystalline
forms, it is polymorphism.

Plot of Cp Vs Time for three formulations of

Chloramphenicol Palmitate
AMORPHISM

 These drugs can exist with no internal

crystal structure.
 Such drug represents the highest energy
state and can be considered as super
cooled liquids and thus have greater
solubility. E.g. Novobiocin.
 Thus, the order of Dissolution & hence
Absorption for different solid dosage
forms is amorphous > meta-stable >
stable.
F) SALT FORM OF THE DRUG

Salt of weak acid and weak

bases have much higher
aqueous solubility than the
free acid or base.

Therefore, if the drug can be

given as a salt, the
solubility can be increased
and the dissolution thus
can be improved. Fig 1. It shows the dissolution
Profile of various salts
 D RUG P K A , LIPOPHILICITY & G I
PH

 According to pH PARTITION THEORY, the process of

absorption of drug compounds of molecular weight
greater than 100 Daltons transported across the
biomembrane by passive diffusion depend upon the
following factor

 Dissociation constant of the drug i.e., pKa of the drug

 Lipid solubility of the unionized drug i.e., Ko/w

 pH at the absorption site

 The amount of drug that exist in unionized form is a

function of dissociation constant(pKa) of the drug and pH
of the fluid at the absorption site.
FOR WEAK ACIDS

FOR WEAK BASE

 PREDICTION BASED ON THEORY

 FOR WEAK ACIDS

 1.very weak acids(pKa>8)– unionized at all ph—absorption is rapid—
indipendantof GI ph
 Eg:-phenytoin , ethosuximide
 2.acids in the pKa range 2.5 to 7.5 largely affected by ph change—
absorption ph dependant—better absorbed from acidic conditions
of stomach (ph<pKa)where they largely exist in unionized form
 Eg:-aspirin , ibuprofen
 3.strong acids (pKa<2.5) ionized at entire ph range of GIT ---remain
poorly absorbed
 Eg:-cromolyn sodium
For basic drugs
1.Very weak bases(pKa<5) unionized at all pH values ---
absorption is rapid and pH indipendant
Eg:-diazepam , nitrazepam

2.Bases in pKa range 5 to 11 is pH dependant –better

absorbed from the
Relatively alkaline conditions of the intestine
Eg:-chloroquine , imipramine

3. Strong bases (pKa>11) ionized at entire pH range –

poorly absorbed
Eg:-mecamylamine guanethidine
1)pH-partition Hypothesis
Simplest principle:

Unionised Higher
Drug: Absorption

Ionised Low
Drug: Absorption
 • Weak Acid pKa>8
High Pentobarbital & aspirin
• Weak Base pKa<5
Absorption (Theophylline, caffeine,
codeine)

Low • Strong Acid(Disodium

cromoglyate)
absorption • Strong Base(Guanethidine)
LIPOPHILICITY

 Only unionized drug having sufficient lipid

solubility is absorbed into systemic circulation.

 So drug should have sufficient aqueous solubility

to dissolve in the fluids at the absorption site and
lipid solubility high enough to facilitate the
partitioning of the drug in lipoidal membrane
and into systemic circulation.
D RUG STABILITY

 Two major stability problems are

 1.degradation of the drug into inactive form

 2.interaction with one or more component

either of the dosage form or those present in the
GIT to form a complex that is poorly soluble
 REFERENCES

 Brahmankar D.M;Jaiswal Sunil.B;

“Biopharmaceutics and Pharmacokinetics–A
Treatise, second edition 2009.

 A Mechanistic Approach to Understanding the

Factors Affecting Drug Absorption: A Review of
Fundamentals Marilyn N. Martinez, PhD, and
Gordon L. Amidon

 overview of factors affecting oral drug

absorption BY Nai –Ning Song, Shao u zhang