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Exposure phase.
Pathways for xenobiotics
Pathways for xenobiotics.
ABSORPTION.
DISTRIBUTION.
STORAGE OF TOXIC SUBSTANCES.
EXCRETION.
•Toxicodynamic
Toxicodynamic PHASE : Toxic Action
substance by interaction with tissue / organ target
S t i t i ti T i ki ti
Systemic toxic action: Toxicokinetics
The study of the movement of toxic species within the body is known as
toxicokinetics.
The toxicokinetic phase encompasses absorption of toxicants into the organism and all
processes which follow, transport by body fluids, distribution and accumulation in
tissues and organs, biotransformation to metabolites and elimination (excretion) of
toxicants and/or metabolites from the organism.
LECTURE 3
THE TRANSIEN THROUGH THE BODY DEPENDS ON
The ability of the xenobiotic to cross cell membranes
The absorption, distribution, and excretion of xenobiotics involves passing
through various cell and organ membranes.
phospholipid
bilayer
y
LECTURE 3
1. ABSORPTION
LECTURE 3. Absorption
Absorption
p mechanisms
CONCENTRATI
PROCESS MECHANISM PRESSURE ON GRADIENT
GRADIENT. CONDITIONS
DEPENDENT
Passive Dilution Not Yes 1. Lipid (distribution
diffusion coefficient lipid / water)
2 Size (Mw)
2.
3. Degree of ionization
(pH and pKa)*
LECTURE 3. Absorption
Absorption mechanisms
Renal excretion:
• Filtration Filtration soluble substance
• Reabsorption: Passive diffusion and Active
Transport
LECTURE 3. Absorption
P
Passage of a xenobiotic from the outside to the biological fluids
f bi ti f th t id t th bi l i l fl id
Gastrointestinal tract, respiratory system and skin
A) Digestive tract
By Passive diffusion
LECTURE 3. Absorption
A) Digestive tract
• liposolubility
p y
Physico-chemical • size (PM)
properties of
substances
• similarity with endogenous molecules
• ionisation of the same or the electric charge
LECTURE 3. Absorption
A) Digestive
Di ti tract
t t
Oral Level
Oral absorption (PH = 7) for Passive diffusion
alcohols nitroglycerin cocaine steroids etc
alcohols, nitroglycerin, cocaine, steroids, etc..
Esophageal Level
Very little absorption occurs
Chemical burns or irritation
LECTURE 3. Absorption
A) Digestive
Di ti tract
t t
Henderson--Hasselbalch Equations
Henderson Equations..
The pKa of a weak acid or weak base is the pH at which there are equal
amounts of the protonated form and the unprotonated form. The Henderson-
Hasselbalch equation can be used to determine the ratio of the two forms
LECTURE 3. Absorption
A) Digestive
Di ti tract
t t
Weak base
[BH+] Ka
For weakk bases,
F b the
h protonated
d
[B] + [H+] form is ionized.
pH = pK ……….[B] = [BH+]
10pH-pK = [B] / [BH+] pH> pKa ……….[B]> [BH+]
pH <pKa………. [B] <[BH+]
LECTURE 3. Absorption
A) Digestive
Di ti tract
t t
Stomach pH = 1
Phenobarbital (weak acid) pKa = 77.22
22
pH-pKa= Log [A-] / [AH]
1-7.22 = log [ -] / [AH]
g [A [ ]
-6.22 = Log [A-] / [AH] ..................... 10 -6.22 = [A-] / [AH]
If [HA] = 1 10 -6.22 = [A-]
The predominated form at pH 1 is nonionized phenobarbital therefore it will
be well absorbed in the stomach.
The stomach, which has high acidity (pH 1-3), is a significant site for
absorption of weak organic acids, which exist in a diffusible, nonionized and
lipid-soluble form. In contrast, weak bases will be highly ionized and
therefore poorly absorbed.
LECTURE 3. Absorption
A) Digestive
Di ti tract
t t
Aniline (weak base) pKa = 5
pH-pK L [B] / [BH+]
H Kto= Log
1-5 = log [B] / [BH+]
-4 = Log [B] / [BH+] ............................ 10 -4 = [B] / [BH+]
If [BH+] = 1 10 -4 = [B]
Ionized aniline predominates at pH 1,
1 therefore it is not practically
absorbed in the stomach.
LECTURE 3. Absorption
A) Digestive
Di ti tract
t t
Enterohepatic
circulation
•Poor absorption
•Exceptions: nicotine and nitroglycerin
•Poor absorption.
absorption Weak Bases
•High absorption. Weak acids
•Chemical breakdown of some substances
•Presence of food
B) RESPIRATORY TRACT
• Route of entry and exit of substances
• Toxicity contact: irritating, caustic or corrosive (NH3, NOx, SOx)
• Target organ of toxic blood (paraquat)
FUNCTIONS • Biotransformations
• Accumulate lipophilic compounds, amines, ethanol
LECTURE 3. Absorption
B) RESPIRATORY TRACT
Inhalation
•The absorption of solid particles, regardless of solubility, is dependent upon
particle size
Large particles are deposited in the nose -
little absorption.
* Small p particles p
penetrate to the alveoli
and can be absorbed.
* Some particles remain in the alveoli
indefinitely. coal dust and asbestos fibers
lead to disease ((ex. asbestosis). )
Both the entry of airborne toxicants into the circulatory system and the distribution to the
body tissues depend upon several factors:
• concentration of the toxicant in the air
• so
solubility
ub ty of
o tthe
e toxicant
to ca t in tthe
ebblood
ood a
andd ttissue
ssue
• the toxicant’s molecular or particular size
• respiration rate
• duration of exposure
• functional integrity
g y of the respiratory
p y tract ((chronic bronchitis,, alveolar breakdown ((emphysema),
p y ),
fibrotic lung disease, and even lung cancer)
LECTURE 3. Absorption
c) SKIN
The skin is is relatively impermeable to most ions as well as aqueous solutions
Epidermis
The outermost layer of cells packed with keratin is called
stratum corneum (cornified layer).
Dermis
–composed primarily of connective tissue.
–Blood vessels are distributed throughout
g the dermis
Also found hair follicles, sweat glands, and sebaceous
glands.
The ability of a toxic substance to penetrate the stratum corneum determines the rate at which
the substance will be absorbed by the skin.
Toxicants move across the stratum corneum by passive diffusion.
Small amounts of chemicals may
y be absorbed through
g the sweat g
glands, sebaceous
glands, and hair follicles.
LECTURE 3. Absorption
c) SKIN
• Factors that influence the absorption of toxicants:
• Damage
D t the
to th integrity
i t it off the ki Abrasion,
th skin Abrasion scratching,
scratching or cuts to the skin
Some acids, alkalis, and corrosives
Burns and dermatitis.
Nonpolar compounds (which are lipid soluble) dissolve in and diffuse through
the lipid material between the keratin filaments
• Solvent as carrier
O
Organic
i chemicals
h i l di dissolved
l d iin water
t d do nott easily
il penetrate
t t ththe skin
ki
Organic solvents, are lipid-soluble and therefore penetrate the cell
membrane readily.
• Molecular size
LECTURE 3. Absorption
2. DISTRIBUTION
The distribution, toxicokinetics second phase, is the passage of the poison from
the blood to the different tissues which exert their action or either accumulate.
LECTURE 3. Distribution
2. DISTRIBUTION
Major distribution of an absorbed chemical is by blood with only
minor distribution by lymph.
LECTURE 3. Distribution
"Total
Total body fluid that would be needed to contain a
toxicant in the body, if it were water soluble and
uniformlyy distributed"
VD = Qt/ Ct Qt = VD· Ct
LECTURE 3. Distribution
2.2. Factors influencing the distribution:
1)Route of exposure
LECTURE 3. Distribution
1) Route of exposure
►Chemicals absorbed through the GIT are
carried directly to the liver
liver, then to the heart
heart,
the lungs then to other organs. “First pass
effect.“(intraperitoneal)
Ej: biotransformation of the propranolol
(cardiac depressant) is about 70% when
given orally.
Over 60% of cardiac
output goes to well‐
Those tissues with increased blood supply will be perfused organs such
more likely to incorporate the toxic from the as liver and lungs.
bloodstream
LECTURE 3. Distribution
Space intracorpuscular
Space
Interstitial
Intravascular space
A B C D
Location:
Liver, spleen and Choroid plexus (eye), H t
Heart muscle,
l Spinal cord,
marrow gastrointestinal mucosa, smooth and brain
kidneys and glands skeletal muscle
LECTURE 3. Distribution
CNS:
P
Penetrate:
t t liposoluble
li l bl substances
b t
Very slowly hydrosoluble and ionized
No pass: compounds linked to plasmatic proteins
LECTURE 3. Distribution
2.2. Factors influencing the distribution:
4)Storage of chemicals in tissues
Storage of chemicals in tissues
g of chemicals within the body
Main sites for storage y are:
• Plasma proteins
• Adipose tissue (fat) Acidic drugs are bound to the most
• Bone abundant plasma
• Liver and kidneys i ((albumin);
protein lb i ) while
hil bbasic
i d
drugs bi
bind
d to
-1-
acid glycoprotein
Plasma protein binding
• Soluble substances
(Ions and small molecules).
They bind to plasma proteins (albumin), transferrin for iron,
ceruloplasmin for copper
• Liposoluble substances or apolar
They bind to lipoproteins (globulins: 1, 2,1, 2, ).
• Substances consigned in
R d Bl
Red Blood
dCCels
l (lead)
(l d)
Transport of Pb
in erythrocytes
LECTURE 3. Distribution
R
Reversible
Reversible binding
ibl bi
binding
bi di
• Reduce the concentration of a unbound states in plasma
(unbound fraction exhibits pharmacologic effects,
effects it may be
metabolized and/or excreted)
•bound state……. no activity.
The xenobiotic‐binding protein acts:
Tampon
p
Reservoir of toxic substances from which the
drug is slowly released
LECTURE 3. Distribution
b)) Lipid
p ((Partition coefficient))
Hg: - inorganic derivatives: in kidney
- Organic derivatives: brain and liver
organochlorine Compounds: Fat tissue
The water-soluble toxics are distributed more or less evenly throughout the
body, and rapidly eliminated.
Liposoluble toxic tends to accumulate in various tissues such as the liver,
liver
adrenal glands, adipose tissue, nerve tissue, etc.
c) Fixation
Fixation: selective chemical affinity
Fluor and lead: accumulate in
bones and interfere with the
metabolism of Ca +2
LECTURE 3. Distribution
3. Elimination
3. Excretion
To a lesser extent
extent::
Lung, breast milk, placenta, sweat, saliva, tears, hair, nails,
skin, etc..
LECTURE 3. Excretion
3.1. Renal excretion
RENAL FILTER:
Blood Flow 1000-1250 mL / min (25% in cardiac output)
y
Ie 1800 L blood / day.
First filtration (primary urine): 130 mL / min = 190 L / day
1% is excreted primary urine: 1
1.5
5 L / day
Hydrosoluble: No protein‐bound
and low PM.
SUBSTANCES
Liposolubles: biotransformations for
increasing polarity
3.1. Renal excretion
A) Glomerular Filtration
B) active tubular Secretion
C) Tubular Resorption
nephron
3.1. Renal excretion
A) glomerular filtration:
Pore glomerular capillaries 70 nm
Pore glomerular capillaries 70 nm
FILTER: Water and solutes.
B) t b l
B) tubular secretion:
tio
Acids, basis and metals by active
transport (T + E).
( )
There is competition for the
transporter (T).
transporter (T)
Greater affinity for T than for
p
plasma proteins.
p
3.1. Renal excretion
C) Reabsorption:
It depends on the pH.
HydroSoluble substances: Urine
LipoSoluble substances: By passive diffusion
Water: By passive diffusion and antidiuretic hormone (ADH)
Glucose and amino acids: by active transport
Increases excretion:
i i lk li i d b HCO3‐
W k id urine is alkalinized by HCO
Weak acids:
Weak Bases: urine is acidified by ClNH4
Plasma Tubule Urine Urine Tubule Plasma
wall Acid pH Basic pH wall
HXH++X- X-+H+HX
Urine pH: range day / night
22. Polar metabolites
3. Differences between species in active secretion and
LECTURE 3. Excretion
reabsorption
3.2. Biliary excretion
Substances Conjugated compounds, polar, nonpolar, non-
ionized, cationic, anionic
Example: flunitrazepam (Ds intake 12 h again passes fewer blood)
Elimination is against a high concentration gradient with specific
Eli i ti i i t hi h t ti di t ith ifi
transporters that can saturate
Enterohepatic circulation:
Liver
Many organic compounds are
combined with glucuronide or
sulfate ions prior to being excreted
in the bile and excreted feces. Transport to
The intestinal microflora can the liver via
portal vein
g
hydrolyze the conjugates to be
reabsorbed (enteroheapatic cycle)
( )
Duodenum
Biliary excretion
By passive diffusion.
Toxic gases and volatile: hydrocarbons
low MW (ethyl ether) alcohols, CO, CNH, etc.
EXCRETION BY FECES
Unabsorbed Ingested substances or
compounds excreted in the bile from the intestinal blood vessels.
Passive diffusion: lipophilic compounds (POC, dioxins and PCBs).
LECTURE 3. Excretion