BIOPHARMACEUTICS

&
PHARMACOKINETICS

GIT: Anatomy and

Physiology

The enteral system consists of the

alimentary canal from the mouth to
the anus.

The major physiologic processes that

occur in the GI system are:
1. secretion
2. digestion
3. absorption

1. Secretion
Secretion includes the transport of
fluid,
electrolytes, peptides and proteins into
the lumen
of the alimentary canal.

1. Secretion

Enzymes in saliva and pancreatic

secretions are involved in the
digestion of carbohydrates and
proteins.
Other secretions such as mucus,
protect the linings of the lumen of the
GIT.

2. Digestion
Digestion breakdown of food
constituents into
smaller structures in preparation for
absorption.
Food constituents are mostly
absorbed in the proximal area
(duodenum) of the small intestine.

3. Absorption
Absorption entry of constituents from
the lumen of the gut into the body; may
be considered as the net result of both
lumen-to-blood and blood-to-lumen
transport movements.

Important:

Drugs administered orally pass through

various parts of the enteral canal
including the oral cavity, esophagus, and
various parts of the GIT. Residues
eventually exit the body through the
anus.

Important:

The total transit time, including gastric

emptying, small intestinal transit and
colonic transit ranges from 0.4 to 5 days
(Kirwan & Smith 1974).
The most important site of drug
absorption is the small intestine.

Important:

Small intestine transit time (SITT)

ranges from 3 to 4 hours for most
healthy subjects. If absorption is not
completed by the time a drug leaves
the small intestine, absorption may be
erratic and incomplete ABSORPTION
WINDOW

Important:

The small intestine is normally filled with

digestive juices and liquids, keeping the
lumen contents fluid.

Important:

In contrast, the fluid in the colon is

reabsorbed, and the luminal content
in the colon is either semisolid or
solid, making further drug dissolution
erratic and difficult.

Important:

The lack of the solubilizing effect of

the chime and digestive fluid
contributes to a less favorable
environment for drug absorption.

The normal physiologic processes of the

alimentary canal may be affected by:

1. diet
2. contents of the GIT
3. Hormones
4. visceral nervous system
5. Disease (diarrhea, inflammatory bowel
disease)
6. Drugs (anticholinergics)

Important:

Thus drugs given by the enteral route

for systemic absorption may be
affected by the anatomy, physiologic
functions and contents of the
alimentary tract.

Important:

Moreover, the physical, chemical and

pharmacologic properties of the drug
itself will also affect its own absorption
from the alimentary canal.

Reasons why GIT offers an efficient

absorption system?
1. copious blood supply
2. entire length of GIT is lined with
mucous membrane
*mucous membrane is rich in blood
vessels and will facilitate absorption of
drug; it secretes mucin which is a high
mw polysaccharide that may bind drugs

Reasons why GIT offers an efficient

absorption system?
3. there are around 8-10 liters of
fluid/day
produced by or secreted into the GIT;
and
1-2 liters come from the food and
fluid
intake.
4. GIT is perfused by capillary network
that
allows efficient absorption and

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Oral Cavity

pH
7

Remarks
Has an average length of 15-20
cm and its main secretion is
saliva (1,500ml/day) which
contain ptyalin, a salivary
amylase and can digest
starches. It also secretes mucin
which is a glycoprotein that may
interact with drugs. Villi is
absent.

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Stomach

pH
Remarks
2-6 Fasting
1.5- Presence of food
2 Secretion histamine (H2) &
gastrin
Gastrin regulated by stomach
distention & presence of
peptides and amino acids

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Stomach

pH

Remarks
Basic drugs are solubilized
rapidly by stomach acid
Emptying is infuenced by food
content and osmolality

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Duodenum

pH
Remarks
6- Presence of bicarbonate
6.5 Trypsin, chymotrypsin &

carboxypeptidase proteins to
amino acids
Amylase CHO
Pancreatic lipase fats to fatty
acids

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Duodenum

pH

Remarks
Complex fluid medium helps
dissolve drugs with limited
aqueous solubility
Ester prodrug are hydrolyzed
Protein drugs are unstable due
to proteolytic enzymes

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Ileum

pH
7

Remarks
Acid drugs will dissolve due to
bicarbonate secretion
Fats and hydrophobic drugs are
dissolved by bile secretion

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Colon

pH
Remarks
5.5- Lack microvilli
7 Very limited drug absorption due
to viscous and semisolid nature
of lumen contents
Mucin lubricant and
protectant

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Colon

pH

Remarks
Theophylline & metoprolol are
absorbed
Absorbed at this region are good
candidates for sustained release
dosage forms
Aerobic & aerobic
microorganisms which
metabolizes drugs (L-dopa and
lactulose)

Biopharmaceutical Data of the

Gastrointestinal Tract

Part
Rectum

pH
7

Remarks
Superior hemorrhoidal vein
Middle hemorrhoidal vein
Inferior hemorrhoidal vein

Transit time of Drug in the

GI Tract

Pharmacologic properties of the drug

Type of dosage form (physicochemical
properties)
Physiologic factors with food
(digestive/fed state) or fasted
(interdigestive state)

Migrating Motor Complex

(MMC)

Alternating cycles of propulsive

movement that empties the upper GI
tract to the cecum

Migrating Motor Complex

(MMC)
I

30-60

II

20-40

Interdigestive (fasted) state

III

10-20

IV

Feeding

0-5

Digestive (fed) state

Migrating Motor Complex

(MMC)

Bile secretion begins at phase II

Onset of particle & mucus discharge may
occur during the latter part of phase II
Mucus & particle discharge continues at
phase III

Functions of Gastric Motility

To allow the stomach to serve as a

reservoir for the large volume of food
that may be ingested at a single meal
To fragment food into smaller particles to
mix chyme with gastric secretion so that
digestion can begin
Empty gastric contents into the
duodenum at a controlled rate (gastric
emptying time)

Factors that affect gastric

emptying

Volume large volume, greater initial

followed by slow emptying
Fatty acids unsaturated > saturated,
14C chain or more > short & medium
chain ? emulsified by bile acid &
lecithin in bile
Carbohydrates hyperosmolar ?
Proteins hyperosmolar ?

Factors that affect gastric

emptying

Osmotic pressure rate of empyting

may increase at lower conc. then
decrease at higher conc.
Physical state of gastric contents
smaller particles ?
Acids ? - low MW > high MW
neutralized by pancreatic & duodenal
secretions

Factors that affect gastric

emptying

Alkali increased at low conc. (1%),

decreased at high conc. (5%)
Drugs- anticholinergic ?, narcotic
analgesic (morphine) ?,
metoclopramide ?, ethanol ?
Body position lying on the left side ?
Viscosity more viscous ?

Factors that affect gastric

emptying

Emotional states aggressive/stressful

state ?, depression?
Bile salts - ?
Exercise - ?
Disease states hypothyroidism vs
hyperthyroidism ?, diabetics ?

Slow in gastric emptying delay in

transit to the duodenum delay in
absorption delay onset of action

Intestinal Motility

Drugs must have a sufficient time

(residence time) at the site for optimum
absorption
Diarrhea absorption of a drug?
Small intestine transit time (SITT)
drug will take about 4-8 hours (fasted
state) & 8-12 hours (fed state) to pass
through the stomach & SI

Intestinal Motility

Mouth-to-anus transit time = 53.3 hours

Mean colon transit time = 35 hours

Perfusion of GI tract

Important in carrying the drug into

systemic circulation
Splanchnic circulation receives about
28% of the cardiac output and is
increased after meals
Some drugs (e.g. bleomycin prepared in
chylomicrons) can be absorbed in
lymphatic circulation and bypass firstpass effect

Effect of Food on GI drug absorption

Delay in gastric emptying

Stimulation of bile flow
Change in pH of the GI tract
An increase in the splanchnic blood flow
Change in the luminal metabolism of
drug substance
Physical or chemical interaction of the
meal with the drug product

Reduced absorption with food

Tetracycline
Penicillin G
Isoniazid
Amoxicillin
Aspirin
Rifampin
Furosemide
Phenacetin

Delayed absorption with

food

Aspirin
Acetaminophen
Nitrofurantoin
Digoxin
Sulfisoxazole
Cephradine
Cefaclor
Sulfadiazine

Increased absorption with

food

Dicoumarol
Griseofulvin
Phenytoin
Metoprolol
Oxazepam
Propranolol
Hydralazine

Not affected with food

Theophylline
Prednisone
Chlorpropramide
Metronidazole
Propylthiouracil

Effect of food on GI drug absorption

Cause
Caloric content
Meal volume
Meal temperature

Effect

Drug product transit time

Luminal dissolution

Drug permeability

Systemic availability

FDA Recommendation

High-calorie and high-fat meals effect

of food on the bioavailability and
bioequivalence of drug products

Effect of Food on GI drug absorption

Penicillin, tetracycline and certain

hydrophilic drugs have decreased
absorption with food
Griseofulvin are absorbed better with
food containing high fat content
Bile increase absorption of fat soluble
drugs through micelle formation

Effect of Food on GI drug absorption

Some basic drugs (cinnarizine) with

limited aqueous solubility can undergo
rapid dissolution and better absorption
in the presence of food acid secretion
pH

Effect of Food on GI drug absorption

Generally, bioavailability of drug is

better in a fasted state and with a larger
volume of water
Drugs (erythromycin, iron salts, aspirin &
NSAIDs) are given with food to reduce
gastric irritaion absorption rate is
reduced but the extent & efficacy is the
same
Unabsorbed antibiotic in the GI tract ?
?
Sustained-release tablet and diarrhea

Effect of Food on GI drug absorption

Enteric-coated tablet vs enteric-coated

beads/microparticles in the presence of
food ? ? drug absorption
Food can affect the integrity of the
dosage form theophylline (controlledrelease tablet) bioavailability more rapid
in the fed-state than fasted-state dose
dumping
Granules ( < 1-2 mm in size) and tablets
that easily disintegrates in the presence
of food ? ?

Effect of food on GI drug

absorption

Timing of taking the meds in relation to

meals H2- blockers
Fatty foods which may delay stomach
emptying ? ? timing of drugs that are
sensitive to acid
pH in relation to drug dissolution
tetracycline and sodium bicarbonate
Food may enhance absorption of drugs
beyond 2 hours after meals (e.g.
cefpodoxime proxetil)

Timing of drug intake in relation to food

Therapeutic goal
Physicochemical properties of the drug
(pka, solubility, particle size, stability in
gastric pH)
Dosage form (sustained-release tablet,
solution, enteric-coated tablet)
Character of the drug (gastric irritant)
Drug interaction/incompatibilities (e.g.
tetracycline + antacids)

Double-peak phenomenon

Usually seen in administered single dose

of fasted patients
Variability of stomach emptying
Variability in intestinal motility
Presence of food
Enterohepatic recycling
Failure of a tablet dosage form

Double-peak phenomenon