PATIENT RELATED FACTORS AFFECTING
DRUG ABSORPTION

M PHARMA 1STYEAR

DEPARTMENT OF PHARMACEUTICS

COLLEGE OF PHARMACY

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CONTENTS

 Anatomy and Physiology of GIT

 Patient related factors affecting drug absorption

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GASTROINTESTINAL TRACT
 The GIT comprises of a number of components, their primary

function being secretion, digestion and absorption.

 The mean length of the entire GIT is 450cm.

 The major functional components of the GIT are stomach, small
intestine (duodenum, jejunum, and ileum) and large intestine
(colon) which grossly differ from each other in terms of anatomy,
function, secretions, and pH.

 The entire length of the GI mucosa from stomach to large
intestine is lined by a thin layer of mucopolysaccharides
(mucus/mucin) which normally acts as an impermeable barrier to
the particulates such as bacteria, cells or food particles.

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STOMACH

 The stomach is a bag like structure having a smooth mucosa and
thus small surface area.

 Its acidic pH, due to secretion of HCL, favours adsorption of
acidic drugs if they are soluble in the gastric fluids since they are
soluble in the gastric fluids since they are unionised to a large
extent in such a pH.

 The gastric pH aids dissolution of basic drugs due to salt
formation.

 The length of the stomach is 20cm.

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SMALL INTESTINE
It is the major site for absorption of most drugs due to its some

characteristics –
 Large surface area -The folds in the intestinal mucosa, called as the

folds of Kerckring, result in 3 fold increase in the surface area.The
surface of these folds possesses finger like projections called as villi
which increase the surface area 30 times. From the surface of villi
protrude several microvilli (about 600 from each absorptive cell that
lines the villi) resulting in 600 times increase in the surface area.

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 Great length of small intestine – It results in more than 200 sqm of
surface which is several times that of stomach.

 Greater blood flow –The blood flow to the small intestine is 6 to 10
times that of stomach.

 Favourable pH range –The pH range of small intestine is 5 to 7.5 which
is favourable for most drugs to remain unionised.

 Slow peristaltic movement – Prolongs the residence time of drug in the
intestine.

 High permeability –The intestinal epithelium is dominated by absorptive
cells.

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LARGE INTESTINE

 Its length and mucosal surface area is very small (villi and
microvilli are absent) in comparison to small intestine.

 Length of large intestine is 110cm.

 The main role of large intestine is in the absorption of water and
electrolytes.

 However, because of the long residence time (6 to 12 hrs), colonic
transit may be important in the absorption of some poorly soluble
drugs and sustained release dosage forms.

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PATIENT RELATED FACTORS
• 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
overgrowth in small intestine.

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 GASTRIC EMPTYING

The passage from stomach to the small intestine,
called as gastric emptying. it can also be a rate limiting step in
drug absorption because the major site of drug absorption is
intestine.

Thus, generally speaking , rapid gastric emptying
increases bioavailability of a drug.

For better dissolution and absorption, the gastric emptying can
be promoted by taking the drug on empty stomach.

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Gastric emptying is a first order process. Several parameters are
used to quantify gastric emptying :

• Gastric emptying rate – It is the speed at which the stomach
contents empty into the intestine.

• Gastric emptying time – It is the time required for the gastric
contents to empty into the small intestine. Longer the gastric
emptying time, lesser the gastric emptying rate.

• Gastric emptying t1/2 – It is the time taken for half the
stomach contents to empty.

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A Large number of factors influence gastric emptying are :
• Volume of meal : Larger the bulk of the meals, longer the gastric

emptying time. However, an initial rapid rate of emptying is
observed with a large meal volume and an initial lag phase in
emptying of a small volume meal. Since gastric emptying is a first
order process, a plot of log of volume of contents remaining in the
stomach versus time yields a straight line

• Composition of meal : Predictably, the rate of gastric emptying
for various food materials is in the following order :

Carbohydrates > proteins > fats
Fats promote secretion of bile which too has an inhibitory effect on

gastric emptying. Delayed gastric emptying as observed with fatty
meals, is beneficial for the absorption of poorly soluble drugs like
griseofulvin.

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 Physical state and viscosity of meal : Liquid meals take less than
an hour to empty whereas a solid meal may take as long as 6 to 7
hrs. viscous materials empty at a slow rate in comparison to less
viscous materials.

 Temperature of the meal : High or low temperature of the
ingested fluid (in comparison to body temperature) reduce the
gastric emptying rate.

 Gastrointestinal pH : Gastric emptying is retarded at low
stomach and promoted at higher or alkaline pH. Chemicals that
affect GI pH also alter gastric emptying.

With alkaline solutions, a low base concentrations (1% NaHCO3)
increases the gastric emptying rate more than the one of higher
concentration (5%).

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 Electrolytes and osmotic pressure :Water, isotonic solutions, and
solutions of low salt concentration empty the stomach rapidly whereas
a higher electrolyte concentration decreases gastric emptying rate.

 Body posture : Gastric emptying is favoured while standing and by
lying on the right side since the normal curvature of the stomach
provides a downhill path whereas lying on the left side or in supine
position retards it.

 Emotional state : Stress and anxiety promote gastric motility whereas
depression retards it.

 Exercise : Vigorous physical training retards gastric emptying.

 Disease states : Disease like gastroenteritis, gastric ulcer, pyloric
stenosis, diabetes and hypothyroidism retard gastric emptying. Partial
or total gastrectomy, duodenal ulcer and hyperthyroidism promote
gastric emptying rate.

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 Drugs : Drugs that retard gastric emptying include poorly
soluble antacids(aluminium hydroxide), anticholinergics
(atropine, propantheline), narcotic analgesics(morphine) and
tricyclic anti-depressents (imipramine, amitriptyline).
Metoclopramide, domperidone, and cisapride (prokinetic-
agents) stimulate gastric emptying.

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 INTESTINAL TRANSIT
Since small intestine is the major site for absorption of most drugs,

long intestinal transit time is desirable for complete drug absorption.

Transit time for contents from different regions of intestine

Intestinal region Transit time

Duodenum 5 minutes

Jejunum 2 hours

Ileum 3 to 6 hours

Caecum 0.5 to 1 hour

Colon 6 to 12 hour

The residence time depends upon the intestinal motility or contractions.
The mixing movement of the intestine that occurs due to peristaltic
contractions promote drug absorption. Firstly, by increasing the drug
intestinal membrane contact and secondly, by enhancing drug dissolution
especially of poorly soluble drugs through induced agitation.

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 GASTROINTESTINAL pH
The GI pH generally increases gradually as one move down the

stomach to the colon and rectum.
GI fluid pH influence drug absorption in several ways :

1. Disintegration : The disintegration of some dosage forms is pH sensitive.
With enteric-coated formulations, the coat dissolves only in the intestine
followed by disintegration of the tablet.

2. Dissolution : A large number of drugs are either weak acids or weak bases
whose solubility is greatly affected by pH. A pH that favours formation of
salt of the drug enhances the dissolution of that drug. Since drug dissolution
is one of the important rate-determining steps in drug absorption, GI pH is
of great significance in the oral bioavailability of drugs. weakly acidic drugs
dissolve rapidly in the alkaline pH of the intestine whereas basic drugs
dissolve in the acidic pH of the stomach. Since the primary site for
absorption of most drugs is small intestine, the poorly water-soluble basic
drugs must first dissolve in the acidic pH of stomach before moving into the
intestine.

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 Absorption : Depending upon the drug pKa and whether its an
acidic or a basic drug, the GI pH influences drug absorption by
determining the amount of drug that would exist in the unionised
form at the site of absorption.

 Stability : GI pH also influences the chemical stability of drugs. The
acidic stomach pH is known to affect degradation of penicillin G
and erythromycin. This can be overcome by preparing prodrugs of
such drugs that do not degrade or dissolve in acidic pH.

ex – carindacillin and erythromycin estolate. With basic drugs,
formation of insoluble drug hydroxide in the alkaline pH of the
intestine has been observed.

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 Disease states : Several disease states can influence the rate and
extent of drug absorption. The 3 major classes of disease states
that can influence the bioavailability of a drug are :

1. Gastrointestinal diseases

2. Cardiovascular diseases

3. Hepatic diseases

1. Gastrointestinal diseases : A number of pathologic conditions
of the GIT can influence changes in drug absorption pattern
namely :

a. Altered GI motility

b. Gastrointestinal disease and infections

c. Gastrointestinal surgery

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• Gastrointestinal diseases and infections : The influence of
achlorhydria (decreased gastric acid secretion and increased
stomach pH) on gastric emptying and drug absorption,
especially that of acidic drugs (decreased absorption, ex –
aspirin) has been studied.

Two of the intestinal disorders related with
malabsorption syndrome that influence drug availability are
celiac disease (characterized by destruction of villi and
microvilli) and crohn’s disease.

GI infections like shigellosis, gastroenteritis,
cholera and food poisoning also result in malabsorption.

colonic diseases such as colitis, amoebiasis and constipation can
also alter drug absorption.

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• Gastrointestinal surgery : Gastrectomy can result in drug
dumping in the intestine, osmotic diarrhoea and reduced
intestinal transit time.

2. Cardiovascular diseases : several changes associated with
congestive cardiac failure influence bioavailability of a drug
via. Oedema of the intestine, decreased blood flow to the
GIT and gastric emptying rate and altered GI pH,
secretions and microbial flora.

3. Hepatic diseases : Disorders such as hepatic cirrhosis
influence bioavailability mainly of drugs that undergo
considerable first-pass hepatic metabolism.

ex – propranolol. Enhanced bioavailability is observed in such
cases

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Blood flow to the GIT :
The GIT is extensively supplied by blood

capillary network and the lymphatic system. The absorbed
drug can thus be taken up by the blood or the lymph.
Since the blood flow rate to the GIT is 500 to 1000 times
more than the lymph flow, most drugs reach the systemic
circulation via blood whereas only a few drugs, especially low
molecular weight, lipid soluble compounds are removed by
lymphatic system.

The high perfusion rate of GIT ensures that once the
drug has crossed the membrane, it is rapidly removed from
the absorption site thus maintaining the sink conditions and
concentrations gradient for continued drug absorption.

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For drugs that have high perfusion rates, ex – highly lipid
soluble drugs or drugs absorbed through pores, the GI perfusion
rate could be a rate-limiting step in the absorption, ex tritiated
water.

This is not so in the case of drugs having a poor
permeability coefficient, ex – ribitol

Blood flow is also important for actively absorbed drugs
since oxygen and energy is required for transportation.

Food influences blood flow to the GIT. The perfusion rate
increases after meals and persists for few hours but drug
absorption is not influenced significantly.

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Gastrointestinal contents

1. Food – drug interactions

2. Fluid volume

3. Interaction of drug with normal GI constituents

4. Drug – drug interaction

1. Food – drug interactions : Presence of food may either
delay, reduce, increase or may not affect drug absorption.

Delayed Decreased Increased Unaffected

Aspirin Penicillins Griseofulvin Methyldopa

Paracetamol Erythromycin Diazepam Propylthiouracil

Diclofenac Ethanol Sulphasomidine

Nitrofurantoin Tetracycline

Digoxin Levodopa

Iron
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Food – drug interactions may be due to the influence of food on
physiological functions (alterations in the GI emptying rate, GI
fluid secretions, pH, blood flow and absorptive processes) and/or
a consequence of physicochemical interaction with the drug
(alteration in drug dissolution profile, complexation and
adsorption).

As a general rule, drugs are better absorbed under
fasting conditions and presence of food retards or prevents it.
Food does not significantly influence absorption of a drug taken
half an hour or more before meals and two hours or more after
meals.

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2. Fluid volume : Administration of a drug with large fluid volume
results in better dissolution, rapid gastric emptying and enhanced
absorption.

Ex – Erythromycin is better absorbed when taken with a glass of water
under fasting condition than when taken with meals.

3. Interactions of drug with normal GI constituents:
The GIT contains a number of normal constituents such as mucin, bile

salts and enzymes which influence drug absorption. Mucin, a
protective mucopolysaccharide that lines the GI mucosa, interacts with
streptomycin and certain quaternary ammonium compounds and
retards their absorption. It also acts as a barrier to diffusion of drugs.
The bile salts aid solubilisation and absorption of lipid soluble drugs
like griseofulvin and vitamins A, D, E and K on one hand and on the
other, decreases absorption of neomycin and kanamycin by forming
water – insoluble complexes.

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4. Drug – drug interactions in the GIT : Like food – drug
interactions, drug – drug interactions can either be physicochemical or
physiological.

a. Physicochemical drug-drug interactions can be due to :
1. Adsorption : Antidiarrhoeal preparations containing adsorbents like

attapulgite or kaolin-pectin retard/prevent absorption of a number of
drugs co-administered with them.

Ex – promazine and lincomycin
2. Complexation : Antacids and/or mineral substitues containing heavy
metals aluminium, calcium, iron, magnesium, or zinc retard absorption
of tetracyclines through formation of unabsorbable complexes.

3. pH change : Basic drugs dissolve in gastric pH; co-administration of
such drugs, ex – tetracyclines with antacids such as sodium bicarbonate
results in elevation of stomach pH and hence decreases dissolution rate
or causes precipitation of drug.

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b. Physiological drug – drug interaction can be due to following
mechanisms :

1. Decreased GI transit : Anticholinergics such as propantheline retard
GI motility and promote absorption of drugs like ranitidine and
digoxin, whereas delay absorption of paracetamol and
sulphamethoxazole.

2. Increased gastric emptying : Metoclopramide promotes GI motility
and enhances absorption of tetracycline, pivampicillin and levodopa.

3. Altered GI metabolism : Antibiotics inhibit bacterial metabolism of
drugs, ex – erythromycin enhances efficacy of digoxin by this
mechanism. Co-administration of antibiotics with oral contraceptives
like ethinyl oestradiol decreases the efficacy of latter by decreasing
enterohepatic cycling of steroid conjugates which otherwise are
hydrolysed by gut bacteria after biliary excretion.

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Presystemic Metabolism / First – pass Effects
For a drug administered orally, the 3 main reasons for its

decreased bioavailability are :

1. Decreased absorption

2. Destabilization or destruction of drug

3. First-pass/presystemic metabolism

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Before a drug reaches blood circulation, it has to pass for the first time
through organs of elimination namely the GIT and the liver.

The loss of drug through biotransformation by such eliminating organs
during its passage to systemic circulation is called as first-pass or
presystemic metabolism.

The diminished drug concentration or rarely, complete absence
of the drug in plasma after oral administration is indicative of first-pass
effects.

The 3 primary systems which affect presystemic metabolism of a drug
are :
1. Luminal enzymes : a. Digestive enzymes

b. Bacterial enzymes
2. Gut wall enzymes/ mucosal enzymes
3. Hepatic enzymes

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1. Digestive enzymes : These are the enzymes present in the gut fluids
and include enzyme from intestinal and pancreatic secretions. The
latter contains hydrolases which hydrolase ester drugs like
chloramphenicol palmitate into active chloramphenicol, and
peptidases which split amide linkages and inactivate
protein/polypeptide drugs. Thus, one of the approaches to effect oral
absorption of peptides is to deliver them to colon which lack
peptidases.

2. Bacterial enzymes : The GI microflora is scantily present in stomach
and smal intestine and is rich in colon. Hence, most orally
administered drugs remain unaffected by them. The colonic microbes
generally render a drug more active or toxic on biotransformation,
ex- sulphasalazine, a drug used in ulcerative colitis, is hydrolysed to
sulphapyridine and 5-amino salicylic acid by the microbial enzymes of
the colon. An important role of intestinal microflora is that in
enterohepatic cycling. Their enzymes hydrolyse the conjugates of
drugs actively secreted via bile such as glucuronides of digoxin and
oral contraceptives. The free drugs are reabsorbed into the systemic
circulation.

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3. Gut wall enzymes : Also called as mucosal enzymes, they are
present in stomach, intestine and colon. Alcohol dehydrogenase
(ADH) is an enzyme of stomach mucosa that inactivates
ethanol. Intestinal mucosa contains both phase 1 and phase 2
enzymes, ex – sulphation of ethinyl oestrdiol and isoprenaline.
The colonic mucosa also contains both phase 1 and phase 2
enzymes. However, it is only the enzymes of the proximal small
intestine that are most active.

4. Hepatic enzymes : Several drugs undergo fiirst-pass hepatic
metabolism, the highly extracted ones being isoprenaline,
propranolol, alprenolol, pentoxifylline, nitroglycerine,
diazepam, nifedipine, lidocaine, morphine etc.

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Reference

Biopharmaceutics and Pharmacokinetics a treatise by
D. M. BRAHMANKAR SUNIL B. JAISWAL

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THANK YOU

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