Physiological Factors
Affecting Oral Absorption
By
A. S. Adebayo, Ph.D.
Objective
At the end of this topic, we should be
able to:
Understand the physiological factors which
affect the oral absorption of drug products
Apply the knowledge to optimization of
patient’s benefit from administered drug
Overall picture of drug absorption,
distribution, and elimination
Davson-Danielli Model
Simplified Model of Membrane
Examples of some
membrane types
Blood-brain barrier
Have effectively no pores in order to
prevent many polar materials (often toxic
materials) from entering the brain.
Smaller lipid materials or lipid soluble
materials, such as diethyl ether, halothane
(used as general anesthetics) can easily
enter the brain.
Renal tubules
Relatively non-porous, only lipid
compounds or non-ionized species
(dependent of pH and pKa) are
reabsorbed.
Placental barrier – find out ??
Blood capillaries and renal glomerular
membranes
Quite porous, allowing non-polar and
polar molecules (up to a fairly large size,
just below that of albumin, (M.Wt
69,000) to pass through.
Especially useful in the kidney since it
allows excretion of polar (drug and
waste compounds) substances.
MECHANISMS OF DRUG TRANSPORT
ACROSS BIOMEMBRANES
 The apical cell membrane of the columnar
absorption cell behaves as a ‘lipoidal’
membrane, interspersed by sub-microscopic
water-filled channels or pores.
 Water soluble substances of small molecular
size (radius 0.4 nm) such as urea are
absorbed by simple diffusion through the
water-filled channels.
MECHANISMS OF DRUG TRANSPORT
ACROSS BIOMEMBRANES
 Most drug molecules are too large to pass
through the aqueous channels.
 The apical cell membrane of the g.i.-blood
barrier allows the passage of lipid-soluble
drugs in preference to lipid-insoluble drugs.
 However, most drugs possess both lipophilic
and hydrophilic entities that enable them to
cross the barrier by the process of “Passive
Diffusion”.
Passive Diffusion
 Involves the movement of drug molecules from
region of relatively high to low concentration without
expenditure of energy.
 Movement continues until equilibrium has been
reached between both sides of the membrane
 the equilibrium tend to be achieved faster with highly
permeable (i.e. lipid soluble drugs) and when membrane has
a large surface area (e.g. intestine vs stomach or
duodenum).
 The apical cell membrane plays only a passive role
in the passive diffusion transport process.
Passive Diffusion (Cont.)
The main factors determining the rate
of drug transport are:
Physicochemical properties of the drug i.e.
particle size, solubility, partition coefficient, pH
and pKa.
The nature of the membrane
The concentration gradient of drugs across the
membrane.
Diagrammatic representation of g.i. absorption by
passive diffusion
G.I
FLUID
BLOOD
G.I.
MEMBRANE
Drug in solution
h
Partition
Diffusion
Partitio
n
Drug in solution
carried away by
circulating blood
Fick’s Law of diffusion
 Where dQ/dt = rate of
appearance of drug in the
blodd at the site of
absorption
 D = the effective diffusion
coefficient of the drug in the
1 g
2 b
gi membrane
 A = the surface area of g.i.
membrane available for
absorption by passive
diffusion
 k1 = the apparent PC of drug
between g.i. ‘membrane’ &
the g.i. fluid.
theconcentration of drug inside themembraneat g.i. fluid/ membraneinterface
k1 
concentration of drug in g.i. fluid
dQ DA(k C  k C )

dt
h
Fick’s Law of diffusion (Cont.)
 Cg is the concentration of drug in solution in
the g.i. fluid at the site of absorption
 k2 is the apparent PC of drug between the g.i.
membrane & the blood
 Cb is the concentration of drug in the blood
at the site of absorption
 h is the thickness of the g.i. membrane.
Fick’s Law of diffusion (Cont.)
 The drug in blood vessel is rapidly cleared away and the blood
thus serves as a “sink” for absorbed drug as a result of:
 Distribution in a large volume of blood i.e. systemic circulation
 Distribution into body tissues and other fluids of distribution
 Metabolism and excretion
 Protein binding
 Hence, a large concentration gradient is always maintained
across the g.i. membrane during absorption process and this
conc. gradient becomes the sole driving force behind drug
absorption by passive diffusion mechanism.
Specialized Transport Mechanisms
Active transport
Facilitated transport
Active transport
 Substances are transported against their
concentration gradient (i.e. from low to high
regions of concentration) across a cell
membrane.
 It is an energy-consuming process and
involves active participation of the apical
cell membrane of the columnar absorption
cell.
Active transport (Cont.)
 Drug molecule or ion forms a complex with a “carrier”
which, may be an enzyme or some other components of
the cell membrane, to form a “drug-carrier” complex.
 This complex then moves across the membrane,
liberates the drug on the other side and the carrier
returns to the original state and surface to repeat the
process.
 As for g.i absorption, transfer occurs only in the direction
of g.i. lumen to the blood i.e. not normally against the
conc. gradient, the carrier being generally a ‘one-way’
transport system.
Active transport (Cont.)
 Several carrier-mediated transport systems exist in the
small intestine and each is highly selective with
respect to the structure of substances it transports.
 Drugs resembling such substances can be transported
by the same carrier mechanism.
 E.g. Levodopa resembles tyrosine and phenylalanine and is
absorbed by the same mechanism.
 Active transport proceeds at a rate directly proportional
to the concentration of the absorbable species only at
low concentration
 the mechanism becomes saturated at high concentrations.
Illustration of Specialized Transport
Facilitated transport
 Differs from active transport in that it can not
transport a substance against its concentration
gradient
 Does not require energy input.
 Its driving force is the concentration gradient.
 Another transport facilitator is required in
addition to the carrier molecule.
Facilitated Transport of Vit. B12
B12
Carrier
IF
B12-IF
Transported Vit.
B12
Receptor-mediated endocytosis
 Process of ligand movement from the
extracellular space to the inside of the cell by the
interaction of the ligand with a specific cellsurface receptor.
 The receptor binds the ligand at its surface
 Internalizes it by means of coated pits and
vesicles
 Ultimately releases it into an acidic endosomal
compartment.
Receptor-mediated endocytosis
Cell
membrane
Free drug
Released drug
Pinocytosis
 Substance does not have to be in aqueous
solution to be absorbed.
 Like phagocytosis, it involves invagination of the
material by the apical cell membrane of the
columnar absorption cell lining the g.i.t. to form
vacuoles containing the material.
 These vacuoles then cross the columnar
absorption cells.
 It is the main mechanism for the absorption of
macromolecules such as proteins and waterinsoluble substances like vit. A, D, E and K.
Convective absorption
 By this mechanism, very small molecules such as water,
urea and low molecular weight sugars and organic
electrolytes are able to cross cell membranes through
aqueous filled channels or pores.
 The effective radii of these channels are small (≈ 0.4 nm)
such that the mechanism is of little significance in the
absorption of large, water-insoluble drug molecules or
ions.
 It is the mechanism involved in the renal excretion of
drugs and the uptake of drugs into the liver.
Ion-pair transport
 In this mechanism, some ionized drug species interact
with endogeneous organic ions of opposite charge to
form absorbable neutral specie i.e. an ion-pair.
 The charges are “buried” in ion pair and the complex can
now partition into the lipoidal cell membrane lining the
g.i.t. and be absorbed by passive diffusion.
 A suitable mechanism for the absorption of quaternary
ammonium compounds and tetracyclines which are
ionized over the entire g.i. pH range.
 Ion pair ≡ Organic anions + Organic cations = Neutral
molecules (crossing lipoidal membrane by passive
diffusion.
Characteristics of G.I physiology
pH
Membrane
BUCCAL
approx 7
Thin
ESOPHAGUS
5-6
Very thick, no
absorption
-
small
1-3
decompos
ition,
weak acid
unionized
Normal
good
small
6 - 6.5 bile
duct,
surfactant
properties
Normal
good
very large
very short (6"
long),
window
effect
no
STOMACH
DUODENUM
Blood Supply
Good, fast
absorption
with low
dose
Surface Area
small
Transit Time
Short unless
controlled
Short
30 - 40
minutes,
reduced
absorption
By-pass liver
Yes
no
SMALL
INTESTI
NE
7–8
Normal
good
very large 10 14 ft, 80
cm 2 /cm
about 3 hours
no
LARGE
INTESTI
NE
5.5 - 7
-
good
not very large 4
- 5 ft
long, up to 24
hr
lower colon,
rectum
yes
Factors that contribute to the intersubject variation in the g.i. pH are
The general health of the individual
The presence of localized disease
conditions (e.g. gastric & duodenal ulcers).
The type and amount of food ingested
Drug therapy (co-administered drugs)
Gastric emptying and motility
Dependence of Peak Acetaminophen Plasma Concentration
as a Function of Stomach Emptying Half-life
Table 2 - Factors Affecting Gastric Emptying
Volume of Ingested Material
As volume increases initially an increase
then a decrease. Bulky material tends to
empty more slowly than liquids
Type of Meal
Fatty food
Decrease
Carbohydrate
Decrease
Temperature of Food
Increase in temperature, increase in
emptying rate
Body Position
Lying on the left side decreases
emptying rate. Standing versus lying
(delayed)
Drugs
Anticholinergics (e.g. atropine)
Decrease
Narcotic (e.g. morphine)
Decrease
Analgesic (e.g. aspirin)
Decrease
Food
Figure 2 - Showing the Effect of Fasting versus Fed
state on Propranolol Concentrations
Effect of food on absorption of some drugs
Drug/dru Reported effect
g group
Comments
Reduced absorption
Atenolol
Food decreases the
extent of absorption
Reduction of about 20% has been reported
Captopril
Food decreases the
extent of absorption
Reduction is 35.5 to 40% and may alter therapeutic effect
Digoxin
Absorption delayed
but total amount
not reduced
The lower rate of absorption is not important this
chronically administered drug; concurrent food intake does
not alter the plasma concentration in patients on
maintenance therapy
Erythromyc
in (base &
stearate)
Rate of absorption
& amount absorbed
are reduced
Extent of absorption of the base and stearate is reduced in
fed state because of acid hydrolysis. Extent of absorption is
higher in the fed state for the more stable estolate derivative.
Effect of food on absorption of some drugs (Cont.)
Increased absorption
Dicumarol
Extent of absorption is
increase by food
Griseofulvin
Absorption increased by
concurrent ingestion of
fatty meal
May be due to dissolution in fat
components and absorption through fat
uptake mechanisms
Phenytoin
Food appears to increase
the rate & extent of
absorption
Changes in extent of absorption can be
dangerous because of saturable hepatic
metabolism.
Propranolol,
metoprolol, labetalol
& hydralazine
Absorption greater in fed
than in fasted state
The low system availability, due to
extensive 1st pass metabolism, is
increased by ≥ 50 %
Effect of Intestinal residence time
 Controlled/sustained/prolonged release dosage
forms as they pass through the entire length of
the g.i.t.
 Enteric coated dosage forms which release the
drug only when in the small intestine
 Drugs which dissolve slowly in the intestinal fluid
 Drugs which are absorbed by intestinal carriermediated transport system.
Drugs affecting gastric emptying rate
Decrease gastric emptying rate
Increase gastric emptying rate
Antihistamines
Anticholinesterases
Antimuscarenic drugs
-Atropine
-Propantheline
Ganglion blocking drugs
- Hexamethonium
Opiod analgesics
- Neostigmine
- Physostigmine
Dopamine antagonists
- Domperidone
- Metoclopramide
- Diamorphine
Iproniazid
Reserpine
- Buprenorphine
Sodium bicarbonate
- Meptazinol
Sumatriptan
- Morphine
Phenothiazines
Sympathomimetics
- Isoprenaline
***END OF PRESENTATION***
QUESTIONS/DISCUSSION