Biopharmaceutic

Lec.3 Absorption of Drug

Assistant Lecturer: Hussein Jabbar

1
M.Sc. (UOB)
Continents
Main factors affecting oral absorption:
I Physiological factors.
II Physical-chemical factors. Next Lecture
III Formulation factors.

I Physiological factors affecting oral absorption:

1- Membrane physiology.
2- Passage of drugs across membranes.
3- Gastrointestinal physiology.
I. Characteristics of GIT physiology and drug absorption
II. Gastric emptying time and motility
III. Effect of food on drug absorption
Physiological factors influencing bioavailability:

1- Membrane physiology:
1- Membrane physiology :
• The cell membrane is the barrier that separates the
inside of the cell from the outside.
• The cell membrane is made up of phospholipids,
proteins, and other macromolecules.
• The phosopholipids make up a bilayer. It contains
hydrophilic and hydrophobic molecules.
• The proteins in the cell membrane are located within
the phospholipid bilayer.
• - So, the biologic membrane is mainly lipid in nature
but contains small aqueous channels or pores.
2-Passage of drugs across membranes:

1- Carrier mediated:
A. Active transport
B. Facilitated transport

2-Passive diffusion
3-Vesicular transport
4- Pore transport
5-Ion pair formation
2-Passage of drugs across membranes:

1- Carrier mediated:
A- Active transport:

- A few lipid-insoluble drugs (e.g.5-flurouracil) that resemble natural

physiologic metabolites (e.g. glucose, amino acids) are absorbed from
the GIT by this process.
- Transport of a drug against concentration gradient (from regions of
low drug concentrations to regions of high concentrations).
- It is an energy-consuming system.

- The carrier molecule may be highly selective for the drug molecule,
therefore, drugs of similar structure may compete for sites of
adsorption on the carrier (competitive inhibition is possible).
- Because only a certain amount of carrier is available, all the adsorption
sites on the carrier may become saturated if the drug concentration
gets very high.
B- Facilitated diffusion:

- Play a very minor role in absorption.

- A drug carrier is required but no energy is necessary. e.g.
vitamin B12 transport.
- Saturable if not enough carrier and structurally selective for
the drug and shows competition kinetics for drugs of similar
structure.
- No transport against a concentration gradient only downhill
but faster.
2- Passive diffusion:

- Most drugs cross biologic membranes by passive

diffusion.
- Diffusion occurs when the drug concentration on one
side of the membrane is higher than that on the other
side.

The rate of transport of drug across the membrane can be

described by Fick's first law of diffusion:-
2- Passive diffusion:

- Most drugs cross biologic membranes by passive

diffusion.
- Diffusion occurs when the drug concentration on one
side of the membrane is higher than that on the other
side.
- The process is passive because no external energy is
expended.
- The driving force for passive diffusion is the
difference in drug concentrations on either side of the
cell membrane.
•The parameters of this equation are:-

D: diffusion coefficient. This parameter is related to the size

and lipid solubility of the drug and the viscosity of the
diffusion medium.
As lipid solubility increases or molecular size decreases then
D increases and thus dM/dt also increases.

A: surface area. As the surface area increases the rate of

diffusion also increase.
The surface of the intestinal lining (with villae and
microvillae) is much larger than the stomach.
This is one reason absorption is generally faster from the
intestine compared with absorption from the stomach.
x: membrane thickness.
The smaller the membrane thickness the quicker the
diffusion process.
As one example, the membrane in the lung is quite thin thus
inhalation absorption can be quite rapid.

(Ch -Cl): concentration difference.

The drug concentration in blood or plasma will be quite low
compared with the concentration in the GI tract. It is this
concentration gradient which allows the rapid complete
absorption of many drug substances.

• Normally Cl << Ch then:-

 carrier-mediated

Relationship between drug concentration and absorption rate

For a passive process (Curve A) and for a carrier-mediated
Process (Curve B).
Illustration of Different Transport Mechanisms
3- Vesicular transport:
- It is the process of engulfing particles by the cell.
- Pinocytosis and phagocytosis are forms of vesicular
transport that differ by the type of material ingested.
Pinocytosis: refers to the engulfment of small molecules or
fluid.
Phagocytosis: refers to the engulfment of larger particles or
macromolecules.
- During pinocytosis or phagocytosis, the cell membrane
invaginates to surround the material, and then engulfs the
material into the cell. Subsequently, the cell membrane
containing the material forms a vesicle or vacuole within
the cell.
- Vesicular transport is the proposed process for the
absorption of Vitamin A, D, E, and K, peptides in new born.
4- Pore (convective) transport:
- A certain type of protein called transport protein may form
an open channel across the lipid membrane of the cell.
- Very small molecules, such as urea, water and sugars are
able to rapidly cross the cell membrane through these
pores.
5- Ion pair formation:
- Strong electrolyte drugs are highly ionized or charged
molecules, such as quaternary nitrogen compounds.
- These drugs penetrate membranes poorly.
- When linked up with an oppositely charged ion, an ion
pair is formed in which the overall charge of the pair is
neutral. This neutral complex diffuses more easily
across the membrane.
- e.g. the formation of an ion pair for propranolol (basic
drug) with oleic acid.
5- Ion pair formation:
3- Gastrointestinal (GI) Physiology:
3- Gastrointestinal (GI) Physiology:
❖The gastrointestinal tract is a muscular tube
approximately 6 m in length with varying diameters.

❖It stretches from the mouth to the anus and consists of

four main anatomical areas: the oesophagus, the stomach,
the small intestine and the large intestine or colon.

❖The majority of the gastrointestinal epithelium is covered

by a layer of mucous.
❖This is a viscoelastic translucent aqueous gel that is
secreted through out the GIT, acting as a protective layer
and a mechanical barrier.
I. Characteristics of GI physiology and Drug Absorption:

Organs pH Membrane Blood Surface Transit By-pass

Supply Area Time liver

Buccal approx thin Good, fast small Short yes

6 absorption unless
with low controlled
dose

Oesophagus 5-6 Very thick - small short, -

no typically a
absorption few
seconds,
except for
some
coated
tablets
 Organs pH Membran Blood Surface Transit By-pass
e Supply Area Time liver
Stomach 1.7-3.5 normal good small 30 min no
(liquid) -
120 min
(solid food)

Duodenum 5-7 normal good Very very short, no

large

Small 6 – 7.5 normal good Very About 3 no

large hours
Intestine

Large 6.8 - 7 - good Not very long, up to Lower

intestine large 24 hours colon,
rectum
yes
I. Characteristics of GI physiology and Drug
Absorption (cont.):
The environment within the lumen:

1-Gastrointestinal pH
- As we observed from the previous tables, the pH of fluids
varies along the length of the GIT.
- The gastrointestinal pH may influence the absorption of
drugs in a variety of ways:
A- It may affect the chemical stability of the drug in the
lumen e.g. penicillin G, erythromycin
B- affect the drug dissolution e.g. weak electrolyte drug.
2-Luminal enzymes
- The primary enzyme found in gastric juice is pepsin.
Lipases, amylases and proteases are secreted from the
pancreas into the small intestine.
- Pepsins and proteases are responsible for the digestion of
protein and peptide drugs in the lumen.
- The lipases may affect the release of drugs from fat / oil –
containing dosage forms.
- Bacteria which are localized within the colonic region of
the GIT secrete enzymes which are capable of a range of
reactions.
- e.g. Sulphasalazine which is a prodrug used to target the
colon.
Bacterial enzymes
Sulphasalazine 5-aminosalycylic acid (Active )
3-Disease state and physiological disorders

1. Local diseases can cause alterations in gastric pH that

can affect the stability , dissolution and absorption of
the drug.
2. Partial or total gastrectomy results in drugs reaching
the duodenum more rapidly than in normal
individuals.
A. This may result in an increased overall rate of
absorption of drugs that are absorbed in the small
intestine.
B. Drugs that require a period of time in the stomach to
facilitate their dissolution may show reduced
bioavailability in such patients.
4-The unstirred water layer

- It is a stagnant layer of water and mucous adjacent to

the intestinal wall.
- This layer can provide a diffusion barrier to drugs.
- Some drugs (antibiotics e.g. tetracycline) are capable
of complexing with mucous, thereby reducing their
availability for absorption.
4-The unstirred water layer
II Gastric emptying and motility:
• The time a dosage form takes to traverse the stomach is
usually termed: the gastric residence time, gastric emptying
time or gastric emptying rate.
• Generally drugs are better absorbed in the small intestine
(because of the larger surface area) than in the stomach,
therefore quicker stomach emptying will increase drug
absorption.
• For example,
A. Good correlation has been found between stomach
emptying time and peak plasma concentration for
acetaminophen.
The quicker the stomach emptying (shorter stomach emptying
time) the higher the plasma concentration.
B. Also slower stomach emptying can cause increased
degradation of drugs in the stomach's lower pH; e.g. L-
dopa.
III Effect of Food:
• The presence of food in the GIT can influence the rate and
extent of absorption, either directly or indirectly via a
range of mechanisms.
A- Complexation of drugs with components in the diet
e.g.Tetracycline forms non-absorable complexes with
calcium and iron, and thus it is advised that patients do not
take products containing calcium or iron, such as milk, iron
preparations or indigestion remedies, at the same time of
day as the tetracycline.
B- Alteration of pH
Food tends to increase stomach pH by acting as a buffer.
This liable to decrease the rate of dissolution and
absorption of a weakly basic drug and increase that of a
weakly acidic one.
C- Alteration of gastric emptying.
• Fats tend to reduce gastric emptying and thus delay
the onset of action of certain drugs.
D- Stimulation of gastrointestinal secretions
A. Pepsin produced in response to food may result in
the degradation of drugs that are susceptible to
enzymatic metabolism, and hence a reduction in
their bioavailability.
B. Fats stimulate the secretion of bile.
Bile salts are surface active agents which increase the
dissolution of poorly soluble drugs (griseofulvin).
Bile salts can form insoluble and non-absorbable
complexes with some drugs, such as neomycin and
kanamycin.
E-Competition between food components and drugs for
specialized absorption mechanisms
• There is a possibility of competitive inhibition of drug
absorption in case of drugs that have a chemical
structure similar to nutrients required by the body for
which specialized absorption mechanisms exist.

F- Increased viscosity of gastrointestinal contents

• The presence of food in the GIT provides a viscous
environment which may result in:
1. Reduction in the rate of drug dissolution
2. Reduction in the rate of diffusion of drug in solution
from the lumen to the absorbing membrane lining
the GIT.
Hence, there is reduction in drug bioavailability.
G- Food-induced changes in presystemic metabolism
• Certain foods may increase the bioavailability of drugs that
are susceptible to presystemic intestinal metabolism by
interacting with the metabolic process.
• E.g. Grapefruit juice is capable of inhibiting the intestinal
cytochrome P450 (CYP3A) and thus taken with drugs that are
susceptible to CYP3A metabolism which result in increase of
their bioavailability.

H- Food-induced changes in blood flow

• Food serve to increase the bioavailability of some drugs (e.g.
propranolol) that are susceptible to first-pass metaolism.-
Blood flow to the GIT and liver increases after a meal.
• The faster the rate of drug presentation to the liver; the
larger the fraction of drug that escapes first-pass
metabolism. This is because the enzyme systems become
saturated.
 Double peak phenomena:
• Some drugs such as cimetidine and rantidine, after
oral administration produce a blood concentration
curve consisting of two peaks.
1. The presence of double peaks has been attributed
to variability in stomach emptying,
2. Variable intestinal motility.
3. Presence of food.
4. Enterohepatic cycle.
5. Failure of a tablet dosage form.
Double peak phenomena:
Pre-systemic metabolism:
• The metabolism of orally administered drugs by
gastrointestinal and hepatic enzymes, resulting in a
significant reduction of the amount of unmetabolized
drug reaching the systemic circulation.

A-Gut wall metabolism

• This effect is known as first-pass metabolism by the
intestine.
• Cytochrome P450 enzyme, CYP3A, that is present in the
liver and responsible for the hepatic metabolism of
many drugs, is present in the intestinal mucosa and that
intestinal metabolism may be important for substrates
of this enzyme e.g. cyclosporin
B-Hepatic metabolism.
B-Hepatic metabolism.
• After a drug is swallowed, it is absorbed by the
digestive system and enters the hepatic portal
system.
• It is carried through the portal vein into the liver
before it reaches the rest of the body.
• The liver metabolizes many drugs (e.g. propranolol),
sometimes to such an extent that only a small
amount of active drug emerges from the liver to the
rest of the circulatory system.
• This first pass through the liver thus greatly reduces
the bioavailability of the drug
Any Question
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