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
distribution of nutrients and drugs.
Biopharmaceutical Data of the Gastrointestinal
Tract
Part pH Remarks
Oral Cavity 7
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 pH Remarks
Stomach 2-6
1.5-
2
Fasting
Presence of food
Secretion histamine (H2) &
gastrin
Gastrin regulated by stomach
distention & presence of
peptides and amino acids
Biopharmaceutical Data of the Gastrointestinal
Tract
Part pH Remarks
Stomach
Basic drugs are solubilized
rapidly by stomach acid
Emptying is infuenced by food
content and osmolality
Biopharmaceutical Data of the Gastrointestinal
Tract
Part pH Remarks
Duodenum 6-
6.5
Presence of bicarbonate
Trypsin, chymotrypsin &
carboxypeptidase proteins to
amino acids
Amylase CHO
Pancreatic lipase fats to fatty
acids
Biopharmaceutical Data of the Gastrointestinal
Tract
Part pH Remarks
Duodenum
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 pH Remarks
Ileum 7
Acid drugs will dissolve due to
bicarbonate secretion
Fats and hydrophobic drugs are
dissolved by bile secretion
Biopharmaceutical Data of the Gastrointestinal
Tract
Part pH Remarks
Colon 5.5-
7
Lack microvilli
Very limited drug absorption due
to viscous and semisolid nature
of lumen contents
Mucin lubricant and
protectant
Biopharmaceutical Data of the Gastrointestinal
Tract
Part pH Remarks
Colon
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 pH Remarks
Rectum 7
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
II III
IV
Feeding
30-60
20-40 10-20
0-5
Interdigestive (fasted) state
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 first-pass 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 (controlled-release 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