Anatomy and Physiology of

Bioavailabilitas per Oral gastrointestinal tract:

correlation to drug absorption
Based on:
Gastrointestinal tract physiology
and its relevance to drug delivery
By David F. EVANS

Biopharmaceutics Phase:
Dosage form
Tablet
IDEAL
Tablet Granules Drug Particles

Therapeutics Practical use

Drug dissolved in GI liquid

Drug Absorbed

intra-venous infusion Per-oral Dosage Form

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 Biopharmaceutics Phase:
GI tract
Tablet

Tablet Granules Drug Particles

Drug dissolved in GI liquid

Drug Absorbed

Gastrointestinal factors relevant to

General Considerations
drug delivery
General considerations gastrointestinal tract four major compartments:
oesophagus,
p g ,
Motility and transit stomach,
small intestine
Gastrointestinal pH colon and rectum together

Additional GI factors related to The common and preferred method of administration of

targeted delivery pharmaceutical compounds oral dosing
Gastrointestinal factors in
Some drugs via the rectum
pathological conditions suppositories
enemas
Summary

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 General Considerations
Mode of delivery for oral dosing:
formulated tablets and liquids to be
absorbed in the mouth or sub-lingually,
liquids, emulsions or elixirs to be
delivered in the stomach or beyond
pellets and microspheres in various
shapes and sizes of uncoated or coated
tablets and capsules.
General Considerations
Because of possible differences in GI
function between health and disease
state, the optimal mode of
administration and absorption of active
pharmacological compounds via the
oral route may also be affected in
different pathological conditions.
General Considerations
Motility,
y, transit time,, p
pH,, chemical
reactions and bacterial metabolism in
each compartment are all factors that
might influence drug dissolution and
absorption and should be considered
in relation to bioavailability of oral
dosage forms.
Motility and transit
Oesophageal motility and transit
Stomach and small intestine
Gastric residence time
Small intestinal transit
Colon and rectum - Motility and transit
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Oesophageal motility and
Stomach and small intestine
transit
The primary physiological role to transport materials
from the mouth to the Stomach
The motility of the stomach and small
The rapid movement ensured by peristalsis of the
smooth muscle wall of the oesophagus even without intestine are governed by two distinct
the assistance of gravity physiological states:
normally rapid and completed in 10-20 seconds after
swallowing the fasting or interdigestive state or
accelerated by water and enhanced by gravity. migrating motor complex (MMC)
Delayed transit is normally only seen in disease states the fed or postprandial state.
that affect motility or lower oesophageal sphincter
relaxation
(achalasia of the cardia and diffuse oesophageal spasm)

Stomach and small intestine Stomach and small intestine

The interdigestive state (MMC) consists of rhythmic
periods of
quiescence,
intermittent contractions
rhythmic contractions of the stomach and small intestine in the
interdigestive period.
In man, these periods cycle through the foregut in
approximately two hours and consist of three distinct
phases.
Phase I is a p period of q
quiescence lasting g from 40 to 60
minutes.
Phase II consists of intermittent contractile activity lasting 40 to
60 minutes,
Phase III culminating in a short burst (5 to 10 minutes) of
regular contractions at a frequency determined by the site of
the activity (12 per minute in the jejunum, 8 per minute in
the terminal ileum)

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Stomach and small intestine
Stomach and small intestine
Stomach and small intestine
Feeding disrupts the interdigestive pattern
which is replaced by a long period of irregular
contractile activity with no apparent rhythm.
This pattern is maintained until the digestion
and absorption of meals is completed and the
fasting pattern then recommences
The next Figure illustrates transition from the
interdigestive to the post-prandial state after
ingestion of a normal, mixed component, solid
meal.
Stomach and small intestine
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Stomach and small intestine
Both the interdigestive and fed pattern of
motility
tilit i
in th
the stomach
t h and d smallll
intestine will affect the rate of gastric
residence time, and the transit of material
through the small intestine.
This should be considered in the
determination of rate and absorption of
orally induced dosage forms.
Stomach and small intestine
In particular, large single units may be
retained
t i d for f many hours
h without
ith t
movement if conditions are suboptimal
for that particle.
Some studies have shown that single
tablets may be delayed for as long as 15
hours in the stomach due to the motility
state at the time of dosing.
Stomach and small intestine
Time of disruption of the fed pattern
governed by many factors including
meal composition (especially lipid content),
caloric load
particle size
In relation to transit of pharmaceutical
d
dosage f
forms, b th the
both th motility
tilit state
t t and
d
the phases of the MMC influence the rate
of movement of orally ingested
compounds along the GI tract.
Gastric residence time
Gastric emptying and gastric residence time of
stomach contents is governed by the nature
and quantity of the ingested material.
Liquids empty more rapidly from the stomach than
solids and non-nutrient liquids more rapidly than
nutrient.
Table 1 illustrates typical
yp gastric emptying
g py g
times for a variety of meals.
The t1/2 time is the period for 50 % emptying of the
meal after ingestion and varies widely from meal to
meal and subject to subject.
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Gastric residence time
Gastric residence time
Davis et al. variation in gastric
emptying between solutions, small
pellets and larger tablets could be as
much as 10 to 12 hours and that
large single units emptied only
during the interdigestive state.
state
Gastric residence time
The antrum of the stomach is of primary
importance in the sampling of particles and
differential antegrade movement or
retropulsion of material larger than the
accepted size for gastric emptying.
The antrum can differentiate between small
and large particles such that gastric emptying
of pellets, tablets and capsules even as small
as 1 mm in diameter can be markedly
influenced by both motility state and the
variation between individuals.
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Gastric residence time Gastric residence time
Coupe et al. the variability of Devereux the density of tablet
gastric
t i emptying
t i off smallll single
i l unit
it f
formulations
l ti can affect
ff t the
th gastric
ti
dosage forms when the residence time and that dense pellets will
administration of tablets and meal be retained for a longer period than
were carefully controlled in normal lighter formulations.
subjects.

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 Gastric residence time Gastric residence time
Caution must therefore be taken in the The danger when the whole day's
administration of single dosage forms and due d
dosage i eventually
is t ll emptied
ti d from
f th
the
consideration given to the nature of the stomach during the interdigestive period
formulation and the time of administration with
regard to meals.
during the night, overdosage is likely.
It is theoretically possible that multiple dosing at minimum result in poor overall long-
of a single large enteric coated dosage form term bioavailability of drug with the
during a day of normal meals with snacks, may resultant sub-optimum efficacy.
result in retention of one or more doses within
the stomach for the whole of the daytime
period.

Colon and rectum - Motility and

Small intestinal transit
transit
Small intestinal transit from the duodenal
Colonic and rectal motilityy and transit is
b lb to
bulb t the
th ileo-caecal
il l valve
l i a more
is
important only if sustained or controlled
predictable phenomena than gastric
release or targeted drugs to the colon are
emptying.
under consideration.
Single units have been shown to transit
Much is left to be discovered regarding
the small intestine at a relatively regular
th physiology
the h i l off colonic
l i motility
tilit and
d its
it
rate with a mean of approximately 3
relation to transit.
hours, although the range is wide (0.5 -
9.5 hrs).

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Colon and rectum - Motility and Colon and rectum - Motility and
transit transit
In addition, it has been shown that even Colonic delivery of drugs must take into
d i colonic
during l i stimulation,
ti l ti iie iin th
the post-
t accountt the
th variable
i bl transit
t it from
f mouth
th to
t
prandial phase, the predominant motility caecum, which we know is mostly
pattern is segmental and there is little net influenced by gastric emptying, but also
movement of colonic content. an unpredictable and variable delay in
transit across the ileo-caecal valve, which
will further influence caecal entry times of
delayed release dosage forms.

Colon and rectum - Motility and Colon and rectum - Motility and
transit transit
Another major factor is the wide
For example,
p , mean caecal to anal transit
diff
differences i movementt across the
in th
time is approximately 36 hours in white
colon and considerations of differential
caucasians on a mixed "western" diet.
colonic movement between liquids and
solid forms, especially in the case of This may vary considerably if diet is high
large single units such as a in fibre or constipation is a problem.
pharmaceutical dosage forms.

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 Colon and rectum - Motility and
transit
By comparison, colo-anal transit may be
as short as 2-3 hours in diarrhoeal or
inflammatory bowel conditions or > 100
hours in pathological constipation.
This variability in transit makes for
difficulties in the accurate placement of
topically acting drugs to the colon,
especially when delivered by the oral
route.
Gastrointestinal pH
The targeting of compounds in this way is
reliant
li t on an accurate t knowledge
k l d off the
th
pH profile along the digestive tract in both
health and disease.
Early studies of gastrointestinal pH
showed a range of pH at different sites in
a small study group of normal subjects
and miscellaneous patients.
Gastrointestinal pH
Enteric coatings that resist gastric acid are
widely used to prevent dissolution of tablets
and microspheres in the harsh environment of
the stomach.
These coatings normally dissolve in a solution
of pH > 6 and therefore release their contents
in the small intestine.
Other coatings have been designed to resist
small intestinal dissolution by a pH resistance
up to pH 7 and above, thus making them ideal
for delivery of drugs to the distal small intestine
and the colon.
Gastrointestinal pH
In 1988, Evans et al., using a stable, accurate
pH telemetry capsule documented pH ranges
along the GI tract in a large group of normal
subjects.
Fig. 2 illustrates the mean and range of pH in
different parts of the gut.
The transition from stomach to small intestine
intestine, ileum
to caecum and differences in right and left colonic
pH are all important factors to be taken into account
in the design of targeted drugs where pH is the
primary mechanism of dissolution.
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Gastrointestinal pH Gastrointestinal pH
The extrapolation of pH data from a
normall healthy
h lth gutt to
t the
th pathological
th l i l
situation must be made with caution.
Recently, other workers using similar
techniques have found that pH variation
may be high in certain diseases.

Gastrointestinal pH Gastrointestinal pH
Gilbert et al. (19) studied jejunal pH in It is likely that some existing systemically
children
hild with
ith cystic
ti fib
fibrosis
i iin relation
l ti tto acting
ti d
drugs may be
b presentedt d in
i the
th
pancreatic supplementation and found future in a targeted form in order to
greater acidification due to the disease. increase efficacy.
Pye et al. (20) studied GI pH in patients Clearly GI pH is a factor which needs
with colorectal neoplasia and found careful consideration in the design of the
greater alkalinisation in the colon. dosage form.

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 Gastrointestinal pH Gastrointestinal pH

Additional GI factors related to Additional GI factors related to

targeted delivery targeted delivery
Azo Bond Azo Bond
Olsalazine is used in the treatment of This
Thi conceptt off inactivating
i ti ti d
drugs whilst
hil t
inflammatory bowel disease. traveling through the upper gut by
temporary binding to other molecules is a
To ensure delivery olsalazine at its novel and attractive concept in the field of
optimum site, that is the colonic mucosa, targeted delivery.
the active molecule is released by Other
Oth compoundsd may be b chemically
h i ll
bacterial degradation of the azo bond bound in this way and released in the
binding twin molecules of olsalazine. colon by bacterial action.

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 Additional GI factors related to
targeted delivery
Amylose
Another possible targeted release
concept has been publicised recently.
The use of resistant-amylose coatings is
considered because of the property of
some forms of amylose that resist
digestion in the small intestine by
amylase.
Gastrointestinal factors in
pathological conditions
An important factor in consideration of
the gastrointestinal tract as a route of
drug administration is alteration of basic
physiology in disease states.
Many diseases can affect the motility and
pH of all parts of the gut as well as the
absorptive efficiency of drugs.
Additional GI factors related to
targeted delivery
Amylose
Digestion however can take place in the
caecum by bacterial breakdown of it and
other polysaccharides.
This property is currently being exploited
to produce resistant coatings for colonic
drug delivery.
Gastrointestinal factors in
pathological conditions
Impairment of one or more of the
important physiological processes may
seriously influence the pattern of
assimilation of pharmacologically active
compounds.
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 Gastrointestinal factors in
pathological conditions
Gastric pH is controlled by acid
secretion
ti within
ithi th
the stomach.
t h pH
H can
alter substantially up to and beyond
neutrality (pH 7).
This can be brought about by some
diseases, with antacids, antisecretory
drugs and ingested food, especially
meals which are highly alkaline.
Gastrointestinal factors in
pathological conditions
Specific GI motor functions that are affected by
diseases are gastric emptying and small
intestinal and colonic transit.
For example, alterations in gastric emptying
can be seen in certain forms of diabetes
mellitus, non-ulcer dyspepsia, post-vagotomy,
p loric stenosis and functional
pyloric f nctional bowel
bo el disorders
including pseudo-obstruction, short bowel
syndrome, and various myopathic and
neuropathic conditions.
Gastrointestinal factors in
pathological conditions
Patients taking enteric coated drugs which rely
on pH or time delay release may well dissolve
in the stomach under certain conditions,
especially when the residence time is long
and/or gastric pH has been altered by one or
more of the above.
For example,
example this is especially important when
the enteric coating prevents gastric mucosal
damage by irritant substances such a non-
steroidal anti-inflammatory drugs.
Gastrointestinal factors in
pathological conditions
In the colon and rectum, chronic idiopathic
constipation may impair the movement of
coated tablets and diarrhoea may accelerate
the tablets to such a degree that they may be
excreted intact.
Inflammatory conditions such as Crohn's
disease and ulcerative colitis influence pH
within the colon and this may be an important
consideration especially in targeted dosage
forms which rely on pH for dissolution.
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 Gastrointestinal factors in
Summary
pathological conditions
Gastrointestinal motility and transit and other
Th
These and d other
h f
factors should
h ld beb factors such as pH,
pH in all compartments of the
digestive tract, should be considered when oral
carefully considered in the design and
dosing of pharmacological compounds is the
development of oral drug therapy. chosen route of administration.
Assimilation and absorption of active
compounds through the gut wall are influenced
by the timing of dosage in relation to meals as
well as the physical nature of the compound.

Summary
Tablet size, density, volume and coating are all
important
p in the timing g and ultimate
bioavailability of drugs.
Control and sustained released and targeted
drugs must also take into account alterations in
gastrointestinal motility affected by pathological
conditions which may affect normal gut
function.
function
Careful consideration of GI tract physiology will
help pharmaceutical scientists in the
development of more efficient and safe delivery
of drugs to the GI tract.

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