Transcript lect. 3.ppt

Dr. Nayira A. Abdel Baky
Associate Professor
Pharmacology and Toxicology
It is the study of the
time course of toxicant
absorption, distribution,
metabolism, and excretion
These are factors affecting :
• Amount of and time a chemical stays at the site of
absorption.
• Rate of absorption and amount absorbed.
• Distribution of the chemical throughout the body.
• Speed of biotransformation and nature of the metabolites
formed.
• Whether a chemical can pass through cell membranes.
• Whether a chemical, or its metabolites are stored in the
body.
• Rate of excretion
— if a chemical is administered faster than it is excreted, it will
accumulate in the body.
ABSORPTION
xenobiotic
EXTERNAL
MEMBRANE
BARRIERS
skin
G.I. tract
lungs
DISTRIBUTION
BLOOD PLASMA
TISSUES
pools
depots
sinks
METABOLISM
EXCRETION
PHASE-1
Oxidation
KIDNEYS
LIVER
lungs
saliva
sweat
breast milk
PHASE-2
conjugation
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Ingestion
Inhalation
Intravenous
Intraperitoneal
Subcutaneous
Gastrointestinal
tract
absorption
Intramuscular
Lung
Dermal
Liver
Blood and lymph
Bile
extracellular
fluid
fat
distribution
Kidney
Bladder
feces
Urine
Lung
soft
tissue
Alveoli
Expired Air
body
organs
Secretory
Structures
bone
excretion
Secretions
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• Absorption is the first step in the toxicokinetics of
a chemical.
• If a toxic substance is not absorbed, it is not a
health hazard.
• Skin, lungs and GIT may be considered as barriers
separating the organisms from the environment
containing chemicals.
• Chemicals must cross one of these barriers to
exert an adverse effect on the body and then pass
through various cell membranes
Route of exposure
The ROUTE (site) of exposure is an important
determinant of the ultimate DOSE –
different routes may result in different
rates of absorption.
Dermal (skin)
Inhalation (lung)
Oral (GI)
Injection
The ROUTE of exposure may be important if
there are tissue-specific toxic responses.
Toxic effects may be local (in a specific tissue)
or systemic (throughout the organism)
Ingestion
Toxicity may be modified by enzymes, pH and
flora…. etc
Respiration
Toxicity may be modified by dissolution in the
blood, volume of distribution…etc
Body surface
Lipid soluble toxicants such as carbon terta
chloride and organophosphate.
Absorption of a substance from the site of
exposure may occur by:
1. Simple diffusion (most common)
Rate of diffusion determined by:
Concentration
Chemistry of the chemical.
2. Facilitated diffusion
3. Active transport
4. Pinocytosis and phagocytosis
► In general, the greater the amount of the
chemical in contact with the absorbing
surface, the greater the amount of the dose
that is absorbed.
• Uncharged molecules may diffuse along
conc. gradient until equilibrium is
reached
• No substrate specific
• Small MW < 0.4 nm (e.g. CO, N20) can
move through cell pores
• Lipophilic chemicals may diffuse
through the lipid bilayer
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First order rate diffusion, depends on
• Concentration gradient
• Surface area (alveoli  25 x body surface)
• Thickness
• Lipid solubility & ionization
• Molecular size (membrane pore size = 4-40 A,
allowing MW of 100-70,000 to pass through)
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dD/dt = KA (Co - Ci) / t
Where;
dD/dt = rate of mass transfer across the membrane
K
= constant (coefficient of permeability)
A
= Cross sectional area of membrane exposed to the
compound
C0
= Concentration of the toxicant outside the membrane
Ci
= Concentration of the toxicant inside the membrane
t
= Thickness of the membrane
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• Carried by trans-membrane carrier
along concentration gradient
• Energy independent
• May enhance transport up to 50,000
folds
• Example: Calmodulin for facilitated
transport of
Ca++
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• Independent of or against conc. gradient
• Require energy
• Substrate –specific
• Rate limited by no. of carriers
• Example: P-glycoprotein pump for xenobiotics
Ca-pump (Ca2+ -ATPase)
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•For large molecules
•Outside: in-folding of cell membrane
•Inside: release of molecules
•Example:
Airborne toxicants across alveoli cells
Carrageenan across intestine
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Must cross several cell layers (stratum corneum,
epidermis, dermis) to reach blood vessels.
Factors important here are:
lipid solubility
hydration of skin
site (e.g. sole of feet vs. scrotum)
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-Newborn (thin delicate skin).
-Lipophilicity
-Cutting , abrasions & dryness of skin
Toxicity
1. Condition of the skin: Stratum corneum serves
as the main barrier. When abraded, increased
absorption will result
2. Skin permeability coefficient
This represents the rate at which a particular drug
penetrates the skin
3. Body region
Not all regions of the body have the same skin
thickness (Forehead versus palm).
4. Lipid solubility
The more lipid soluble the drug is the more it will
be absorbed
5. Skin hydration
For gases, vapors and volatile liquids,
aerosols and particles
In general: large surface area, thin barrier,
high blood flow
rapid absorption
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1-Solubility of the drug in the blood
2-Particle size
Large particles are deposited in the nasal tract
> 5 microns; 2-5 micron particles are
deposited mainly in the tracheobronchial
region; while particles less than 1 micron
penetrate into the alveolar sacs and
absorbed into the blood
3. Water solubility
High water solubility volatile drugs are
absorbed in the nasal tract; while low
water solubility drugs will reach the
bronchioles to alveoli
Absorption can occur at any point along the
GIT, however, the degree of absorption at a
particular site depends on the chemical
(a) Mouth and oesophagus
Little absorption occurs due to the short time the chemical
remains there, exceptions include nitroglycerin.
(b) Stomach
-Weak organic acids are absorbed from the acidic medium in
the stomach. Some other drugs can be also absorbed in the
stomach, e.g. alcohol , aspirin .
--The acid may break some chemicals down.
(c) Small intestine
Absorption of alkaline chemicals (and food) is greatest from
small intestine. soluble molecules are absorbed by diffusion.
– Carrier mediated mechanisms exist for some larger
chemicals.
(d)Colon and rectum
Little absorption takes place here
-Disintegration of dosage form and dissolution of
particles
-Stability of chemical in gastric and intestinal juices
and enzymes
-Rate of gastric emptying
-Presence and type of food
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• Rapid process relative to absorption
and elimination
• Extent depends on
- blood flow
- size, M.W. of molecule
- lipid solubility and ionization
- plasma protein binding
- tissue binding
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Main mechanisms opposing distribution of the
toxicants are:
a-Plasma proteins
b-Storage
c-Special barriers (B.B.B.)
Alter plasma binding of chemicals
1000 molecules
A
99.9
1
% bound
molecules free
B
90.0
100
B has 100-fold increase in free
pharmacologically
active concentration at site of action than A.
NON-TOXIC
TOXIC
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Competition-displacement between xenobiotics
Extracellular
Fluid
low
bioavailability
high
Bioavailability and toxicity
capillary wall
Blood
Plasma
ac tive molecules
free in solution
inactive molecules
bound to albumin
Al bumi n
Al bumi n
Al bumi n
Al bumi n
tolbutamide
(hypoglycemic drug)
drug 1 ( )
moderate affinity
for plas ma albumin
binding sites
drug 2 ( )
greater affinity for
plasma albumin
binding sites
tolbutamide
+
warfarin
(antocoagulant)
Displacement of one highly bound drug by another
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Barriers to movement of chemicals from blood into
tissues
• Blood-brain barrier.
Many toxic chemicals are prevented from entering
the brain by a BBB.
•Placental barrier
The placenta transports nutrients from the mother
to the fetus and wastes from the fetus to the
mother.The placenta protects the developing fetus
from many chemicals in the maternal circulation.
•Blood-testis barrier
Protects the developing sperm from some chemicals
brain capillaries are unfenestrated -no gaps
cell membrane of capillary
endothelium cells sealed shut
tight intercellular junctions constitute
the blood brain barrier (BBB)
hydrophiles dissolved in blood
typically cannot pass through the
BBB into brain
Astrocyte
Endothelial cell
lipophiles can easily permeate the
BBB by transcellular permeation
(passive diffusion)
Tight junction
Basal membrane
(porous)
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-Some toxicants are stored in inert tissues (e.g.
bone, fat, hair, nail) to reduce toxicity
-Lipophilic toxicants (e.g. DDT) may be stored in
milk at high conc and pass to the young
Toxicant
Pb
Cd
DDT
Target organs
Bone, teeth, brain
Kidney, bone, gonad
Adipose tissue
Aflatoxin
Liver
-Convert toxicants into more water soluble form
(more polar & hydrophilic)
-Dissolve in aqueous/gas phases and eliminate by
excretion (urine/sweat) of exhalation.
-May increase or decrease toxicity of toxicants after
transformation (e.g turn Benzo[a]pyrene into
benzo[a]pyrene diol epoxide, and nitroamines into
methyl radicals)
-Inducible and inhibited by toxicants
-Sequestrate in inactive tissues (e.g bone, fat)
-Gas (e.g. ammonia) and volatile (e.g. alcohol)
toxicants may be excreted from the lung by
simple diffusion
-Water soluble toxicants may be excreted through
the kidney by active or passive transport
-Conjugates with high molecular wt. may be
excreted into bile through active transport
-Lipid soluble and non-ionised toxicants may be
reabsorbed (systematic toxicity)
Elimination
of chemicals from the body
KIDNEY
LIVER
filtration
secretion
metabolism
excretion
(reabsorption)
LUNGS
OTHERS
exhalation
mother's milk
sweat, saliva etc.
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MOTHER’S MILK
a) By simple diffusion mostly. Milk has high lipid
content and is more acidic than plasma (traps
alkaline fat soluble substances).
b) Important for 2 reasons: transfer to baby,
transfer from animals to humans.
OTHER SECRETIONS – sweat, saliva, etc..
minor contribution
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