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ADME - ABSORPTION
Dr Basma Damiri
Toxicology
105447
Exposure
• Exposure is the presentation of the xenobiotic (chemical
foreign to the body) to the individual. Units of exposure to
xenobiotics are usually parts per million (ppm) or a unit of
weight per cubic meter of air, liter of water, or kilogram of
food (diet).
• Dermal exposures are usually expressed as
concentrations of the solution in contact with a surface
area, (for example, micrograms per square centimeter).
Dose
• Dose is the amount of xenobiotic that reaches the target
organ to elicit a chemical reaction that takes place
between the toxicant and an endogenous compound in or
on the target cell.
• Units of dose are usually given as a unit of weight
administered per kilogram body weight or square meter of
body surface area (same as exposure).
Absorption
• one must always consider two aspects of absorption:
• 1) transport from the body surface into the blood (or
lymph) and
• 2) from the blood into the tissues.
Absorption
GI
• GI is one of the most important sites for toxicants
absorptions.
• The gastrointestinal tract (GIT) is a hollow tube (lined by a
layer of columnar cells, and usually protected by mucous,
which offers minimal resistance to toxicant penetration.
• The distance from the outer membrane to the vasculature
is about 40 μm, from which point further transport can
easily occur. However, the cornified epithelium of the
esophagus prevents absorption from this region of the
GIT.
• Most of the absorption will therefore occur in the intestine
(pH = 6), and to some extent in the stomach (pH = 1–3).
Buccal and rectal absorption can occur in special
circumstances.
• If the toxicant is an acid and base, it tends to be absorbed
by simple diffusion in the part of GI tract where it exist in
the most lipid soluble or non-ionized form.
• Organic bases, in contrast, are largely ionized at the pH of
the stomach contents, and so are much more efficiently
absorbed from the intestine.
• Absorption from GI is strongly site –dependent,
• pH 1-3 in stomach and 5-8 in small intestine and colon.
• Absorption of organic acids (pKa) 3-5: well absorbed in acidic
environment such as the stomach.
• Epithelial cells in the GI tract are specialized in absorption and
elimination
• Most of the absorption in the GIT is by passive diffusion,
except for nutrients; glucose, amino acids, and drugs that
look like these substances are taken up by active
transport.
• For toxicants with structural similarities to compounds
normally taken up by these active transport mechanisms,
entry is enhanced.
• For example, cobalt is absorbed by the same active
transport mechanism that normally transports iron, and 5bromouracil is absorbed by the pyrimidine transport
system.
pKa for SA is 2
Small intestine has closer pH to blood, the most
important part for absorption.
Non-ionized =100
Ionized= 1000000
2-1=1
2-7=-5
-5= log 100/1000000
1= log
[nonionized]/[ionizedd]
Factors important in determining whether and how rapidly a
compound will be absorbed from the GI tract:
1. Physical factors:
• Lipid solubility
• Molecular size
Both determine the rate of diffusion on non-ionized species.
2. The presence of villi which increase the surface area to
the volume.
3. The toxicant that mimic molecular size, configuration,
and charge distribution of essential nutrients may be
transported by carrier process already in the place of
absorption of the nutrient

5- fluorouracil is absorbed by pyrimidine transport
mechanism.
4. What will happen to the compounds that are not stable
at the acid pH of the stomach?
5. What can the intestinal microflora do to chemicals?
6. The rate at which foodstuffs pass through the GI tract?
GIT motility has a significant effect on GIT absorption of a
toxicant. For example, excessively rapid movement of gut
contents can reduce absorption by reducing residence time
in the GIT, while the presence of food in the stomach can
delay the progress of drugs from the stomach to the small
intestine where most of the absorption will occur.
Increased splanchnic blood flow after a meal can result in
absorption of several drugs (e.g., propranolol), but in
hypovolemic states, absorption can be reduced.
4. Fasting: absorption increases at short period of fasting
but my fall off by long time fasting as a result of low
blood flow.
5. Chemical and physical characteristics of the compound
such as its solubility under the conditions present in the
GI and its interaction with other compounds.
6. Age and nutritional status of the individual.
7. First-pass metabolism enzymes can inactivate some
chemicals after they metabolized them such as phase I
and II enzymes.
Biotransformation in the GIT prior to absorption can have a
significant impact on bioavailability of a toxicant.
Skin -2nd major pathway of absorption
• It is a barrier because of
• keratinized layer of thick walled epidermis cells (stratum corneum).
• Many layers
• stratum corneum can provide as much as 80% of the
resistance to absorption to most ions as well as aqueous
solutions. However, the skin is permeable to many
toxicants, and dermal exposure to agricultural pesticides
and industrial solvent can result in severe systemic
toxicity.
• The dermis and subcutaneous areas of the skin are less
important in influencing penetration, and once a toxicant
has penetrated the epidermis, the other layers are
traversed rather easily.
• A number of appendages are associated with the skin,
including hair follicles, sebaceous glands, eccrine and apocrine
sweat glands, and nails. Recently it was found that removal of
the stratum corneum does not allow complete absorption; thus
it is apparent that some role, although of lesser importance, is
played by other parts of the skin.
• Passive diffusion
• The ease with which a compound penetrates the skin is
correlated with its partition coefficient.
• ↑ partition coefficient  ↑ penetration
• For a toxicant to pass the skin
• Moderately lipophilic log Kow 3,4
• Low MW< 300 dalton
• Nicotine 162 dalton
Factors affect skin absorption:
• Capillary blood flow/ temperature.
• Abrasion.
• Hydration of the skin
• DMSO
Good question for the exam:
• Glyceryl trinitrate patch used in the treatment and
prevention of angina is administered dermally but not
orally? Why
• Name some toxicant that can cause systemic injury by
percutaneous absorption?
• Variations in areas of the body cause appreciable
differences in penetration of toxicants.
• The rate of penetration is in the following order:
Scrotal > Forehead > Axilla >= Scalp > Back = Abdomen >
Palm and plantar.
ABSORPTION OF TOXICANTS BY THE LUNGS
In the early (1493-1541), a famous toxicologist Paracelsus
described the relationship between mining occupations and
pulmonary toxicity in the sixteenth century
Anatomy
Three basic regions:
• the nasopharyngeal region,
• the tracheobronchiolar region,
• and the distal or alveolar region.
Terms
• Aerosol solid or liquid particles (fine drops or droplet)
•
•
•
•
•
that are suspended in the air from a mixture.
Dust consist of particles in the solid phase.
Fumes- chemical change in a compound during
processes such as welding.
Smokes- consist of particles of both solid and some
times liquid phase and the associated gases that result
from combustion.
Smog- Smokes and Fog
Mists (small droplets of water suspended in air
condensing on other particles)
What is a Particulate Mater
(PM)?
PM is a complex
mixture of solid,
semi-volatile and
aqueous
materials of
various sizes
found in the air.
ABSORPTION OF TOXICANTS BY THE
LUNGS
• Water-soluble gases dissolve in the mucus lining the
respiratory tract and can accumulate there, causing local
damage;
• lipid-soluble gases diffuse across the alveolar membrane
at a rate dependent upon the lipid/water partition
coefficient and solubility of the gas in blood.
Particle size
Size is the primary critical determinant of how much and
where the agents will be deposited.
• Dust: up t0 100 µm
Å to 0.1 µm
• Smokes: less than 0.5µm
• Fumes: from 10
Airways have branched bifurcations
• Airway split into two with each decrease in
internal diameter.
• Increases surface area and decreases the speed or
the velocity of air flow so the particles become
heavier and precipitate.
• Site of toxicity
Airways
have
branched
bifurcations
cartilage
goblet cells
mucus-producing glands
ciliated epithelium
Levitzky, 1995
• Aerosols are absorbed according to the size of the
particles and their aerodynamic properties, lipid/water
partition coefficients, and several other factors.
• Particles more than 10 μm in diameter usually impact in
the upper airways, especially the nasal turbinates and
trachea.
• Particles between 1 to 5 μm in diameter impact in the
lower bronchioles and alveolar ducts.
• Particles less than 1 μm in diameter usually reach
alveolar sacs.
• Absorption of water -soluble chemicals in the lung and
even in the nasal cavity, can be quite high.
• Aspirin found to be 100 percent bioavailable from the rat
nasal cavity but only 59% bioavailable if given orally.
Individual particles come in many shapes and
sizes
Mineral Fiber
Anthropogenic PM
Natural Fiber
Pollen
Particle shape
• Most of particles are not spherical but highly irregular in
shape.
Clearance of particles will decrease
absorption
• In nasopharyngeal and tracheobronchial region-
Mucociliary escalator mechanism.
• In the respiratory wall – pseudostratified columnar
epithelial cells together with specialized goblet cells,
Cilia.
Absorption of gases and vapors
• Limiting factors: Solubility vs perfusing in lungs
• Effect of solubility:
•
• Rate of blood flow:
•
• Increasing the rate of respiration (ventilation),
•
• ventilation-limited vs flow limited compounds in their
absorption characteristics.
Application:
• What will happen to chloroform once it is inhaled?
Chloroform is lipid- soluble. Is chloroform a ventilation or
flow limited compound? Why?