Anatomic and Physiological

Consideration in Oral Drug Absorption

Fakultas Farmasi Universitas Jember

 Gastrointestinal Tract
• The GIT comprises of a
number of components,
their primary function
being secretion (Saliva
enzymes, pancreatic
enzymes, mucus
secretion), digestion and
absorption.
• The mean length of the
entire GIT is 450 cm. The
major functional
components of the GIT are
stomach, small intestine
(duodenum, jejunum and
ileum) and large intestine
(colon).
 Oral Cavity
• Saliva is the main secretion of the oral cavity, and it
has a pH of about 7. Saliva contains ptyalin (salivary
amylase), which digests starches. Mucin, a
glycoprotein that lubricates food, is also secreted and
may interact with drugs. About 1500 mL of saliva is
secreted per day.
 Esophagus
• The esophagus connects the pharynx and the cardiac
orifice of the stomach.
• The pH of the fluids in the esophagus is between 5
and 6. The lower part of the esophagus ends with the
esophageal sphincter, which prevents acid reflux
from the stomach.
 Stomach
• The fasting pH of the stomach is about 2 to 6. In the
presence of food, the stomach pH is about 1.5 to 2, due
to hydrochloric acid secreted by parietal cells.
• Basic drugs are solubilized rapidly in the presence of
stomach acid.
• Food and liquid are emptied by opening the pyloric
sphincter into the duodenum.
• Stomach emptying is influenced by the food content
and osmolality. Fatty acids and mono - and diglycerides
delay gastric emptying.
• High-density foods generally are emptied from the
stomach more slowly.
b
 Duodenum
• A common duct from the pancreas and the gallbladder
enters into the duodenum.
• The duodenal pH is about 6 to 6.5, because of the
presence of bicarbonate that neutralizes the acidic chime
emptied from the stomach
• Trypsin, chymotrypsin, and carboxypeptidase are involved
in the hydrolysis of proteins into amino acids.
• Amylase is involved in the digestion of carbohydrates.
Pancreatic lipase secretion hydrolyzes fats into fatty acid.
• The duodenum is a site where many ester prodrugs are
hydrolyzed during absorption.
 Jejunum
• The jejunum is the middle portion of the small
intestine, between the duodenum and the ileum.
• Digestion of protein and carbohydrates continues
after addition of pancreatic juice and bile in the
duodenum.
• This portion of the small intestine generally has
fewer contractions than the duodenum and is
preferred for in-vivo drug absorption studies.
 Ileum
• The ileum is the terminal part of the small intestine.
This site has fewer contractions than the duodenum
and may be blocked off by catheters with an
inflatable balloon and perfused for drug absorption
studies.
• The pH is about 7, with the distal part as high as 8.
Due to the presence of bicarbonate secretion, acid
drugs will dissolve. Bile secretion helps to dissolve
fats and hydrophobic drugs.
b
 Colon
• The colon lacks villi and has limited drug absorption
also, because of the more viscous and semisolid
nature of the lumen contents.
• The colon is lined with mucin that functions as
lubricant and protectant.
• The pH in this region is 5.5 to 7.
• A few drugs, such as theophylline and metoprolol,
are absorbed in this region.
• Drugs that are absorbed well in this region are good
candidates for an oral sustained-release dosage form
 Rectum
• The rectum is about 15 cm long, ending at the anus.
• In the absence of fecal material, the rectum has a small
amount of fluid (approximately 2 mL) with a pH about 7.
• The rectum is perfused by the superior, middle, and
inferior hemorrhoidal veins.
• The inferior hemorrhoidal vein (closest to the anal
sphincter) and the middle hemorrhoidal vein feed into
the vena cava and back to the heart. Drug absorption
after rectal administration may be variable, depending
on the placement of the suppository or drug solution
within the rectum
 Drug Absorption in GIT
• Drugs may be absorbed by passive diffusion from all
parts of the alimentary canal including sublingual,
buccal, GI, and rectal absorption.
• For most drugs, the optimum site for drug
absorption after oral administration is the upper
portion of the small intestine or duodenum region.
• In addition, the duodenal region is highly perfused
with a network of capillaries, which helps to
maintain a concentration gradient from the intestinal
lumen and plasma circulation.
 Gastric Emptying
• The passage from stomach to the small intestine,
called as gastric emptying, can also be a rate-limiting
step in drug absorption because the major site of
drug absorption is intestine.
• Rapid gastric emptying is advisable where;
– A rapid onset of action is desired e.g. sedatives
– Dissolution of drug occurs in the intestine e.g. enteric
coated dosage forms
– The drugs are not stable in the gastric fluids e.g. penicillin
G and erythromycin
– The drug is best absorbed from the distal part of the small
intestine e.g. vitamin B12
• Delay in gastric emptying is recommended
particular where;
– The food promotes drug dissolution and absorption
e.g. griseofulvin
– Disintegration and dissolution of dosage form is
promoted gastric fluids
– The drugs dissolve slowly e.g. griseofulvin
– The drugs are absorbed from the proximal part of
the small intestine and prolonged drug-absorption
site contact is desired eg; vitamin B2 and vitamin C
 Factors Influencing Gastric Emptying

1. Volume of meal
2. Composition of meal
3. Physical state and viscosity of meal
4. Temperature of the meal
5. Gastrointestinal pH
6. Electrolytes and osmotic pressure
7. Body posture
8. Emotional state
9. Exercise
10. Disease state
11. Drugs
 Intestinal Transit
Small intestine transit time (SITT)about 3 to 4 hours.
Thus a drug may take about 4 to 8 hours to pass
through the stomach and small intestine during the
fasting state. During the fed state, SITT may take 8
to 12 hours. Delayed transit is desirable for:
– Drugs that dissolve or release slowly from their dosage
form (sustained release products)
– Drugs that dissolve only in the intestine (enteric
coated formulations)
– Drugs absorbed from specific sites in the intestine
(several B vitamins)
 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 as
disintegration, dissolution, absorption and stability.
 Disease States
• Drug absorption may be affected by any disease that
causes changes in (1) intestinal blood flow, (2)
gastrointestinal motility, (3) changes in stomach
emptying time, (4) gastric pH that affects drug
solubility, (5) intestinal pH that affects the extent of
ionization, (6) the permeability of the gut wall, (7)
bile secretion, (8) digestive enzyme secretion, or (9)
alteration of normal GI flora.
 Blood Flow to the GIT.
• 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
concentration gradient for continued drug absorption.
• 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
(28% of cardiac output) more than the lymph flow, most
drugs reach the systemic circulation via blood whereas
only a few drugs, especially low molecular weight, and
lipid soluble compounds are removed by lymphatic
system.
 Gastrointestinal Contents
A. Food-drug interactions
• Presence of food may either delay, reduce, increase or may
not affect drug absorption.
• 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.
• Delayed gastric emptying, affecting drugs unstable in the
stomach e.g. penicillins, eritromycine
• Formation of a poorly soluble, unabsorbable complex e.g.
tetracycline-calcium
• Increased viscosity due to food thereby preventing drug
dissolution and/or diffusion towards the absorption site
• Increased drug absorption following a meal could be
due to one or more of the under mentioned reasons:
– Increased time for dissolution of a poorly soluble drug
– Enhanced solubility due to GI secretions like bile
– Prolonged residence time and absorption site contact of
the drug e.g. water-soluble vitamins
– Increased lymphatic absorption e.g. acitretin
B. Fluid volume
• Administration of a drug with large fluid volume
results in better dissolution, rapid gastric emptying
and enhanced absorption.
• For example, erythromycin is better absorbed when
taken with a glass of water under fasting condition
than when taken with meals.
C. Interaction 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 Gl
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
solubilization 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.
D. Drug-Drug interactions in the GIT
– Physicochemical of drug-drug interactions
• Adsorption
• Complexation
• pH change
– Physiological drug-drug interactions
• Decrease GI transit
• Increased gastric emptying
• Altered GI metabolism
 Decreased absorption, and
First-pass/presystemic metabolism.
• 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 4 primary systems which affect presystemic
metabolism of a drug are;
– Lumenal enzymes
– Gut wall enzymes/mucosal enzymes,
– Bacterial enzymes, and
– Hepatic enzymes.
 Absorption of Drugs From Non Per Oral

Route Bioavailability
Parenteral routes
Intravenous Complete (100%) systemic
bolus (IV) drug absorption Rate of bioavailability
considered instantaneous
Intravenous Complete (100%) systemic
infusion (IV inf) drug absorption
Rate of drug absorption controlled
by infusion pump
Intramuscular Rapid from aqueous solution
injection (IM)
Slow absorption from non-aqueous
(oil) solutions
Subcutaneous Prompt from aqueous solution
injection (SC) Slow absorption from repository
formulations
Enteral routes
Buccal or Rapid absorption from
sublingual (SL) lipid-soluble drugs
Oral (PO) Absorption may vary Generally
slower absorption rate compared
to IV bolus or IM injection
Rectal (PR) Absorption may vary from
suppository
More reliable absorption
from enema (solution)
Other routes
Transdermal Slow absorption, rate may vary
Increased absorption with
occlusive dressing
Inhalation Rapid absorption Total dose
absorbed is variable
Intraocular The barrier for penetration is the cornea
administration Viscosity imparters increase bioavailability
Oily solution, ointments and gels sustained drug
action
Vaginal administration Intended for locally treatment
Systemic delivery of contraceptive without the
disadvantage of first-pass metabolism
 Pertanyaan Tugas
1. Apakah yang menyebabkan perbedaan kecepatan dan jumlah
obat yang diabsorbsi dari berbagai area GIT?
2. Mengapa semua tipe obat baik asam, basa, atau netral baik
diabsorbsi di usus ?
3. Obat obat apa sajakah yang memerlukan waktu pengosongan
lambung yang cepat ?
4. Apakah yang menyebabkan peningkatan absorbsi dan
penundaan absorbsi obat jika dikonsumsi setelah makan ?
mengapa studi biofarmasi dilakukan pada sukarelawan dalam
keadaan perut kosong ?
5. sebutkan dan jelaskan berbagai area yang memungkinkan
presistemik metabolisme pada pemberian obat per oral !