2 c2 Final Factors Affecting Oral Drug Absorption-1

II.
Factors affecting oral

drug absorption
II. Factors affecting oral drug
absorption
Objective of the session:

♂ list the factors affecting oral drug
absorption
♂ explain patient related factors effect on
oral drug absorption
♂ explain how patient related factors
affect oral drug absorption
II. Factors affecting oral drug absorption
Drug absorption
♣ the oral route of drug administration is the most
common for systemically acting drugs
 natural & convenient for the patient,
 relatively easy to manufacture oral dosage
forms
↔ more emphasis given to GI absorption of
drugs
II. Factors affecting oral drug absorption
I. Pharmaceutical factors
A. chemical factors
B. Physicochemical properties of drug
C. Formulation factors
II. PATIENT RELATED FACTORS

D. PHYSIOLOGICAL FACTORS
1. Member physiology
2. Gastero-intestinal motility
3. Age
B. CLINICAL FACTORS
A. chemical factors
 Free form vs salt form

 Example penicillin salt form vs free form
 Salt form enhance solubility
B. Physicochemical properties of drug

1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Salt forms
5. Ionization
6. Drugs pka and lipophilicity and GI PH
Drug solubility and dissolution rate
Salt form of drug
• enhance the dissolution and absorption rate

of certain drugs is by formation of in – situ salt
formation
Drug pKa & lipophilicity & GI pH ---
C. Formulation factors
1. Disintegration time
• Rapid disintegration is important to have a rapid absorption so
lower D.T is required.
• Now D.T of tablet is directly proportional to
–amount o f binder
-Compression force.
2. Manufacturing variables
1. Method of granulation
2. Compression force
3. Nature and types of dosage forms
3. Nature and types of dosage forms
Schematic representation of the processes involved in drug
therapeutics
4. Pharmaceutical ingredients/Excipients
• More the no. of excepients in dosage form, more complex it is &

greater the potential for absorption and Bioavailability problems
• a) Vehicle-
• b) Diluents-
– Hydrophilic diluents-form the hydrophilic coat around hydrophobic drug
particles –thus promotes dissolution and absorption of poorly soluble
hydrophobic drug.
• c) Binders & granulating agent -
– Hydrophilic binders – imparts hydrophilic properties to granule surface –
better dissolution of poorly wettable drug.
– More amount of binder – increases hardness of tablet – decrease
dissolution & disintegration rate.
• d) Disintegrants -
• e) Lubricants -
• f) Suspending agents/viscosity
5. Product age and storage conditions
• Product aging and improper storage

conditions adversely affect B.A.
• E.g. –precipitation of drug in solution decrease
rate of Change in particle size of suspension
drug dissolution & Hardening of tablet
Patient related factors
[A] PHYSIOLOGICAL FACTORS
1. Membrane physiology
A. Nature of cell membrane
B. Transport processes
2. Gstero-Intestinal Physiology
(A) Gastric emptying rate:-
• Factors that influence gastric emptying rate are: -
a. Volume of meal
b. Composition of meal
c. Physical state and viscosity of meal
d. Temperature of meal
e. Gastrointestinal pH
f. Electrolyte and osmotic pressure
g. Body posture
h. Emotional state
i. Disease state.
1. Physiologic factors
GI Tract
♣ related to the
 anatomical,
 physiological and
 pathological
characteristics of the
patient
Intestinal motility
 Normal peristaltic movements mix the contents of the
duodenum, bringing the drug particles into intimate contact
with the intestinal mucosal cells.
 The drug must have a sufficient time (residence time) at the
absorption site for optimum absorption. In the case of high
motility in the intestinal tract, as in diarrhea, the drug has a very
brief residence time and less opportunity for adequate
absorption.
Drug stability in GIT
 Metabolism or degradation by enzymes or chemical
hydrolysis may adversely affect the drug absorption and thus
reduces B.A.
 Destruction in gastric acid.
 Generally a problem with orally administered drugs
Intestinal transit: -
 Long intestinal transit time is desirable for complete absorption
of drug e.g. for enteric coated formulation & for drugs absorbed
from specific sites in the intestine.
 Peristaltic contraction promotes drug absorption by increasing

the drug membrane contact and by enhancing dissolution
especially of poorly soluble drugs.
 Influenced by food, disease and drugs. e.g. metoclopramide
enhance absorption of rapidly soluble drugs
 while anticholinergic retards intestinal transit and promotes the
absorption of poorly soluble drugs.
Effect of Food
• Some effects of food on the bioavailability of a drug
from a drug product include ():
– Delay in gastric emptying
– Stimulation of bile flow
– A change in the pH of the GI tract
– An increase in splanchnic blood flow
– A change luminal metabolism of the drug
substance
– Physical or chemical interaction of the meal with
the drug product or drug substance
• The absorption penicillin and tetracycline, is decreased with food;
whereas other drugs, particularly lipid-soluble drugs such as
griseofulvin and metazalone, are better absorbed when given with
food containing a high fat content.
 Propranolol plasma concentrations are larger after food than in
fasted subjects.
 This may be an interaction with the components of food.
pH and surface area of GIT:
2) Age
• In infants, the gastric pH is high and intestinal surface
and blood flow to the GIT is low resulting in altered
absorption pattern in comparison to adults.
• In elderly persons, causes of impaired drug absorption
include altered gastric emptying, decreased intestinal
surface area and GI blood flow, higher incidents of
achlorhydria and bacterial over growth in small
intestine.
Clinical Factors:-
B. Clinical Factors
1. Diseases
 Parkinson's disease
 Achlorhydricpatients
 Congestive heart failure (CHF) patients
 Crohn's disease
2. Drugs
 Anticholinergic drugs
 Metoclopramide
 Antacids
 Cholestyramine
Factors vs drug absorption ……………..
§ Different factors affect the rate and extent of

oral drug absorption:
A. Primary factors:
♣ the three primary factors that influence drug
absorption
a) permeability,
b) solubility, and
c) dissolution
Physiologic factors ……………..
GIT anatomy and physiology
The GIT: § four main anatomical

§ stretches from the areas:
mouth to the anus 1. esophagus,
§ a muscular tube 2. stomach,
§ approximately 6 m 3. small intestine
in length with 4. large intestine or
varying diameters colon
1. Oesophagus
♣ extends from the pharynx to the stomach
♣ muscular tube of approximately 25cm in length
and 2cm in diameter
♣ the oesophageal transit is extremely rapid (10-
14 seconds)
♣ the pH of the oesophageal lumen is usually
between 5 & 6
♣ primarily as a transport medium between
compartments
2. Stomach
§ located just left of the midline
between the oesophagus and
small intestine
§ divided into 4 anatomical
regions:
 fundus, body, antrum &
pylorus
§ a capacity of approximately 1.5
L
§ contains mostly gastric
Function:
§ to act as a temporary reservoir
§ to reduce ingested solids to a
uniform creamy consistency
(chyme)
 by the action of acid and
enzymatic digestion.
3. Small intestine
§ extend from the pyloric sphincter of the stomach
to the ileocaecal junction where it joins the large
intestine
§ the longest (4-5 m), pH (6-7.5)
§ divided into the:
 duodenum: 200-300 mm
 jejunum: 2 m
 ileum: 3 m
The wall of the small intestine

 rich network of both blood and lymphatic vessels
 receive blood from the superior mesenteric
artery via branched arterioles
 blood leaving: flows into the hepatic portal vein
 liver  systemic circulation
 In small intestine
§ different sub-mucosal folds, villi & microvilli, HCO3,
NaHCO3, mucus, bile, enzymes (hydrolases, proteases)

 Main functions:
a. digestion: the process of enzymatic digestion,

b. absorption: the most nutrients and other materials are
absorbed
4. Colon:
§ the final part of GIT
§ stretches from the ileocaecal junction to the
anus
§ makes up approximately the last 1.5 m
♣ no specialized villi
♣ surface area remains approximately l/30th that
of the small intestine
The main functions of the colon:

♣ the absorption of sodium ions, chloride ions
and water
♣ the storage and compaction of faeces
♣ A number of patient related factors affects drug

absorption rate & extent
1) age
2) gastric emptying 6) blood flow
time through the GIT
3) intestinal transit 7) GI contents
time (foods, drugs,
4) gastrointestinal enzymes),
pH 8) The GI
1. Age:
 Physiological difference
Example: Newborns have:

 less acidic gastric fluids,
 smaller gut fluid volume,
have relatively
 slower gastric emptying rate, lower drug
 less intestinal surface area and absorption
 less intestinal blood flow
2. The transit of pharmaceuticals in the GIT

♣ transit times through certain regions of the GIT can
affect drug behavior, such as absorption
♣ Example:
a. gastric emptying
b. small intestinal transit
c. colonic transit
a. Gastric emptying of pharmaceuticals
♣ time needed for the stomach to empty the total initial stomach
contents/ dosage form
♣ usually range between 5 minutes & 2 hours
♣ dependent on the:
 dosage form
 fed/fasted state of the
stomach
 postural position,
 composition of the food,
 effect of drugs & disease
state
b. Small intestinal transit

♣ relatively constant, at around 3 hours
♣ does not discriminate between dosage forms, or
between the fed and the fasted state
♣ particularly important for dosage forms that
release their drug slowly (e.g. controlled-
sustained- prolonged-release systems)
c. Colonic transit
♣ long and vary from anything between 2 & 48 hours
♣ depends on the type of dosage form, diet, eating
pattern and disease state
In most individuals mouth-to-anus transit

times are longer than 24 hours
3. Gastrointestinal pH
♣ may influence the absorption of drugs in a
variety of ways:
♣ chemical stability of the drug in the lumen,
E.g. degradation of penicillin G gastric pH
♣ dissolution or its absorption, if the drug is a

weak electrolyte
4. Luminal enzymes
♣ pepsin in gastric juice
♣ lipases, amylases & proteases in the small
intestine
♣ responsible for most of nutrient digestion &
other drugs that resemble nutrients, such as
nucleotides and fatty acids
5. food in the GIT

§ influence the rate and extent of absorption, either directly or
indirectly via a range of mechanisms
1. Complexation of drugs with components in the diet
#Tetracycline forms non-absorbable complexes with calcium
and iron
2. Alteration of pH by acting as a buffer
3. Alteration of gastric emptying: e.g. fat
4. stimulation of gastrointestinal secretions

5. competition between food components and
drugs for specialized absorption mechanisms
6. food-induced changes in blood flow: ↑flow to GIT
& liver
7. food-induced changes in presystemic
metabolism
 Grapefruit juice, inhibiting the intestinal
cytochrome P450 (CYP3A family)
6. Disease state and physiological disorders

♂ local diseases can cause alterations in gastric
pH
♂ gastric surgery can cause drugs to exhibit
differences in bioavailability than that in normal
individuals
7. Gastrointestinal membrane
♣ the main cellular barrier to the absorption of
drugs from the GIT to systemic circulation
♣ semipermeable
♣ complex in nature: composed of lipids, proteins,
lipoproteins and polysaccharides
♣ permeable to amino acids, sugars, fatty acids
and other nutrients, and impermeable to plasma
proteins
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II.

Factors affecting oral

Objective of the session:

II. PATIENT RELATED FACTORS

 Free form vs salt form

B. Physicochemical properties of drug

• enhance the dissolution and absorption rate

• More the no. of excepients in dosage form, more complex it is &

• Product aging and improper storage

 Peristaltic contraction promotes drug absorption by increasing

§ Different factors affect the rate and extent of

The GIT: § four main anatomical

The wall of the small intestine

§ different sub-mucosal folds, villi & microvilli, HCO3,

NaHCO3, mucus, bile, enzymes (hydrolases, proteases)

a. digestion: the process of enzymatic digestion,

The main functions of the colon:

♣ A number of patient related factors affects drug

Example: Newborns have:

2. The transit of pharmaceuticals in the GIT

b. Small intestinal transit

In most individuals mouth-to-anus transit

♣ dissolution or its absorption, if the drug is a

5. food in the GIT

4. stimulation of gastrointestinal secretions

6. Disease state and physiological disorders

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