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TOXICOKINETICS
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Toxicokinetics - the study of the time
course of toxicant absorption,
distribution, metabolism, and excretion
How can we predict variability among individuals?
How can we extrapolate from animal models to humans?
Dosage
Exposure
Plasma Site of
action
Conc.
Toxicokinetics
Toxic
Effects
Toxicodynamics
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Toxicokinetic (TK) processes
ABSORPTION
xenobiotic
EXTERNAL
MEMBRANE
BARRIERS
skin
G.I. tract
lungs
DISTRIBUTION
BLOOD PLASMA
TISSUES
pools
depots
sinks
METABOLISM
PHASE-1
Oxidation
PHASE-2
conjugation
EXCRETION
KIDNEYS
LIVER
lungs
saliva
sweat
breast milk
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Disposition of Xenobiotics
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
Secretory
Structures
soft
tissue
Alveoli
Expired Air
body
organs
Secretions
bone
excretion
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Structural model of cell membrane
The ‘lipid sieve’
model explain how
lipophilic small
cpds can permeate
through the
membrane by
passive diffusion
HYDRO
PHILE
EXTERIOR
HYDRO
PHILE
HYDRO
PHILE
polar heads
HYDRO
PHILE
non-polar tails
LIPOPHIL E
Phospholipid
Bilayer
hydrophilic cpds
cannot permeate
unless there is a
specific membrane
transport channel
or pump.
INTERIOR
FACILITATED DIFFUSION
OR
ACTIVE TRANSPORT
HYDRO
PHILE
PASSIVE
DIFFUSION
LIPOPHIL E
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Mechanism of Membrane
Permeation
1.
2.
3.
4.
Passive diffusion
Active transport
Facilitated transport
Pinocytosis
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Transfer of Chemicals across Membranes
PASSAGE ACROSS
MEMBRANES
Passive
Facilitated
Active
Passive transport determined
by:
- Permeability of surface
- Concentration gradient
- Surface area
Permeability depends on:
For cell membranes:
- Lipid solubility
- pH of medium
- pK of chemical
For endothelium
size, shape and charge of
chemical
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Uptake by Passive diffusion
• Uncharged molecules may diffuse along
conc. gradient until equilibrium is
reached
• No substrate specific
• Small MW < 0.4 nm (e.g. CO, N20,
HCN) can move through cell pores
• Lipophilic chemicals may diffuse
through the lipid bilayer
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Rate of Absorption
The rate of absorption determines the time of
onset and the degree of acute toxicity. This is
largely because time to peak (Tmax) and
maximum concentration (Cmax) after each
exposure depend on the rate of absorption.
Rate the following processes in order of fastest to
slowest: INTRAVENOUS> INHALATION >ORAL
> DERMAL EXPOSURE.
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Factors Affecting Absorption
Determinants of Passive Transfer (lipid
solubility, pH, pK, area, concentration
gradient).
Blood flow
Dissolution in the aqueous medium
surrounding the absorbing surface.
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Factors Affecting GI Absorption
Disintegration of dosage form and
dissolution of particles
Chemical stability of chemical in gastric
and intestinal juices and enzymes
Rate of gastric emptying
Motility and mixing in GI tract
Presence and type of food
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Lungs Absorption
For gases, vapors and volatile liquids,
aerosols and particles
In general: large surface area, thin barrier,
high blood flow
rapid absorption
Blood:air partition coefficient –
influence of respiratory rate and blood flow
Blood:tissue partition coefficient
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Lungs Absorption
REMOVAL OF
PARTICLES
Physical
Lymph
Phagocytosis
Absorption of Aerosols and
Particles:
1- Particle Size
2- Water solubility of the
chemical present in the
aerosol or particle
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Airway anatomy
bronchial tree
trachea
•
•
diffusion distance: ~20 mm
total exchange gas exchange area: ~80 m2
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Airway anatomy
trachea
alveoli
capillaries
bronchial tree
•
•
diffusion distance blood/air: ~20 mm
total exchange gas exchange area: ~80 m2
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Absorption Area in the Respiratory System
Nasopharynge
5-30 µm
Trachea
Bronchi
Bronchioles
1-5 µm
Alveolar Region
1 µm
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Skin Absorption
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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Other Routes of Exposure
Intraperitoneal
large surface area, vascularized, first
pass effect.
Intramuscular, subcutaneous,
intradermal: absorption through
endothelial pores into the circulation;
blood flow is most important + other
factors
Intravenous
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Bioavailability
Definition: the fraction of the administered
dose reaching the systemic circulation
for i.v.: 100%
for non i.v.: ranges from 0 to 100%
e.g. lidocaine bioavailability 35% due to
destruction in gastric acid and liver metabolism
First Pass Effect
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FIRST PASS
EFFECT
Intestinal vs.
gastric
absorption
Wilkinson, NEJM 2005
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Extent of Absorption or Bioavailability
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
Dose
to
systemic
circulation
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Principle
For xenobiotics taken by routes other than the
iv, the extent of absorption and the
bioavailability must be understood in order to
determine whether a certain exposure dose
will induce toxic effects or not. It will also
explain why the same dose may cause toxicity
by one route but not the other.
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Distribution
Distribution is second phase of TK
process
defines where in the body a xenobiotic will go after
absorption
Perfusion-limited tissue distribution
perfusion rate defines rate of blood flow to organs
highly perfused tissues (often more vulnerable)
liver, kidneys, lung, brain
poorly perfused tissues (often less vulnerable)
skin, fat, connective tissues, bone, muscle (variable)
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Distribution into body
compartments
• Plasma 3.5 liters. (heparin, plasma expanders)
• Extracellular fluid 14 liters.
(tubocurarine, charged polar compounds)
• Total body water 40 liters. (ethanol)
• Transcellular small. CSF, eye, fetus (must
pass tight junctions)
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Distribution
• 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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Distribution
Initial and later phases:
initial determined by blood flow
later determined by tissue affinity
Examples of tissues that store
chemicals:
fat for highly lipid soluble
compounds
bone for lead
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Volume of Distribution (Vd)
Volume into which a drug appears
to distribute with a concentration
equal to its plasma concentration
Amount of drug in body
Vd =
Concentration in Plasma
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Examples of apparent Vd’s for some
drugs
Drug
L/Kg
L/70 kg
Sulfisoxazole
0.16
11.2
Phenytoin
0.63
44.1
Phenobarbital
0.55
38.5
Diazepam
2.4
168
7
490
Digoxin
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Distribution
Blood Brain Barrier – characteristics:
1. No pores in endothelial membrane
2. Transporter in endothelial cells
3. Glial cells surround endothelial cells
4. Less protein concentration in
interstitial fluid
Passage across Placenta
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Normal blood capillaries
most capillaries are fenestrated
small gaps in capillary wall
not tightly sealed
allows paracellular permeation of
small plasma solutes
hydrophiles can pass thru capillary
wall into tissue ECF
must be smaller than 100 A
lipophiles cannot easily permeate
capillary wall by paracellular
permeation
mostly bound to plasma proteins
permeate capillary wall by
passive diffusion in free plasma
phase
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Brain capillaries: blood-brain barrier (BBB)
brain capillaries are
unfenestrated -- no gaps
cell membrane of capillary
endothelium cells sealed shut
tight intercellular junctions
constitute the blood brain
barrier (BBB)
paracellular permeation of
plasma solutes is impossible
hydrophiles dissolved in blood
typically cannot pass through
the BBB into brain
lipophiles can easily permeate
the BBB by transcellular
permeation (passive
diffusion)
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Capillary structure
General circulation
Central nervous system:
‘blood brain barrier’
Endothelial cell
Tight junction
Basal membrane
(porous)
Astrocyte
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Elimination
Includes all mechanisms for
removing xenobiotics from the body
Kel is the elimination rate constant

One compartment model


Slope = -kel/2.3
Two Compartment model
 = distribution Constant
 slope = ß/-2.3 and is the elimination rate
constant


Is calculated after pseudoequilibrium has been
established
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Clearance (CL)
Defined rate xenobiotic
eliminated from the body

Can be defined for various
organs in the body
Sum of all routes of elimination

CLtotal = CLliver + CLkidney + CLintestine

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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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Elimination by the Kidney
Excretion - major
1) glomerular filtration
glomerular structure, size constraints,
protein binding
2) tubular reabsorption/secretion
- acidification/alkalinization,
- active transport, competitive/saturable
organic acids/bases,
-protein binding
Metabolism - minor
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Nephron Structure
(A.C. Guyton, Textbook of Medical Physiology, Philadelphia, W.B. Saunders Co.; 1991
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Elimination by the Liver
Metabolism - major
1) Phase I and II reactions
2) Function: change a lipid soluble to
more water soluble molecule to excrete
in
kidney
3) Possibility of active metabolites with
same or different properties as parent
molecule
Biliary Secretion – active transport, 4
categories
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The enterohepatic shunt/
circulation
Drug
Liver
Bile
Bile formation
duct
Biotransformation;
Hydrolysis by
glucuronide
beta glucuronidase
gall bladder produced
Portal circulation
Gut
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EXCRETION BY OTHER ROUTES
LUNG - For gases and volatile liquids by
diffusion.
Excretion rate depends on partial pressure of gas
and blood:air partition coefficient.
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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Toxicokinetic parameters
Vol of distribution
V = DOSE / Co
Plasma clearance
CL = Kel .Vd
plasma half-life (t1/2)
t1/2
= 0.693 / Kel
or directly from graph
Bioavailability
F
=
(AUC)x / (AUC)iv
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CONCLUSION
The absorption, distribution and
elimination of a chemical are qualitatively
similar in all individuals. However, for
several reasons, the quantitative aspects
may differ considerably. Each person must
be considered individually and treated
accordingly.
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