Transcript Plasma concentration

TOXICOKINETICS
Dr: Wael Hamdy Mansy
Department of Pharmacology
King Saud University
1
Toxicokinetics - the study of
the time course of toxicant
absorption, distribution,
metabolism, and excretion
Dosage
Exposure
Plasma Site of
action
Conc.
Toxicokinetics
Toxic
Effects
Toxicodynamics
2
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 bilayer
model explain how
HYDRO
PHILE
EXT ERIOR
lipophilic
xenobiotics can
permeate through
the membrane by
passive diffusion
HYDRO
PHILE
HYDRO
PHILE
polar heads
HYDRO
PHILE
LIPOPHILE
Phospholipid
Bilayer
hydrophilic
xenobiotics can’t
permeate unless
there is a specific
membrane
transport channel
or pump.
non-polar tails
INT ERIOR
FACILITATED DIFFUSION
OR
ACTIVE TRANSPORT
HYDRO
PHILE
PASSIVE
DIFFUSION
LIPOPHILE
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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
Passive 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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Facilitated Transport
• 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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Active Transport
• Independent of or against conc. gradient
• Require energy
• Substrate –specific
• Rate limited by no. of carriers
• Example: P-glycoprotein pump for xenobiotics (e.g.
oleoresin capsicum or OC gas ) and Ca-pump (Ca2+ -
ATPase).
10
Uptake by Pinocytosis
For large molecules ( ca 1 um)
Outside: in-folding of cell membrane
Inside: release of molecules
Example:
Airborne toxicants across alveoli cells
Carrageenan across intestine
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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.
Quiz: 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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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
Intravenous
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Bioavailability
Definition: the fraction of the administered
dose reaching unchanged to 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
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FIRST PASS EFFECT
Intestinal vs.
gastric absorption
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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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Plasma concentration
70
60
Bioavailability (F)
(AUC)o
(AUC)iv
i.v. route
50
40
oral route
30
20
Time (hours)
10
0
0
2
4
6
8
10
20
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 11 liters.
(tubocurarine, charged polar compounds)
• Intracellular water 28 liters.
• Total body water 42 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
25
Alter plasma binding of chemicals
1000 molecules
99.9
% bound
90.0
1
molecules free
100
100-fold increase in free pharmacologically
active concentration at site of action.
NON-TOXIC
TOXIC
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volume of distribution
Chemicals appear to distribute in the body
as if it were a single compartment.
The magnitude of the chemical’s
distribution is given by the apparent volume
of distribution (Vd).
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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
28
29
Co
V = Dose / Co
Ln of
Blood (or
Plasma)
Conc.
Time
Vd can be calculated after an IV dose of a substance that
exhibits "one-compartment model" characteristics.
Vd = Dose / Initial Conc
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Examples of apparent Vd’s for some drugs
L/Kg
L/70 kg
Sulfisoxazole
0.16
11.2
Phenytoin
0.63
44.1
Phenobarbital
0.55
38.5
Diazepam
2.4
168
Digoxin
7
490
Drug
31
Competition-displacement between xenobiotics
Extracellular
Fluid
low
bioavailability
high
bioavailability
capillary wall
Blood
Plasma
active 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 plasma albumin
binding sites
drug 2 ( )
greater affinity for
plasma albumin
binding sites
tolbutamide
+
warfarin
(anticoagulant)
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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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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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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
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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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Quantitative Aspects of
Toxicokinetics
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Plasma Concentration
12
TOXIC RANGE
10
8
THERAPEUTIC RANGE
6
4
2
SUB-THERAPEUTIC
0
0
1
2
3
4
5
6
7
8
9
Dose
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Plasma concentration
Variations in Rates of Absorption and Elimination on
Plasma Concentration of an Orally Administered
Chemical
14
12
10
8
6
4
2
0
0
5
10
15
20
TIME (hours)
42
Example of one or two
compartment model
43
Two Compartment Model
Assumes xenobiotic
enters the first
compartment
Assumes that xenobiotic
is distributed to the
second compartment
and a
pseudoequilibrium is
established
Elimination is from the
first compartment
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Elimination
Zero order: constant rate of
elimination irrespective of plasma
concentration.
First order: rate of elimination
proportional to plasma concentration.
Constant Fraction of drug eliminated
per unit time.
Rate of elimination = constant (CL) x Conc.
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Zero Order Elimination
Pharmaco-Toxicokinetics of Ethanol
Mild intoxication at 1 mg/ml in plasma
How much should be taken in to reach it?
42 g or 56 ml of pure ethanol (Vd x Conc.)
Or 120 ml of a strong alcoholic drink like whiskey
Ethanol has a constant rate of elimination of
10 ml/hour
To maintain mild intoxication, at what rate must
ethanol be taken now?
at 10 ml/h of pure ethanol, or 20 ml/h of drink.
DRUNKENNES
RARELY DONE
S
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Plasma Concentration
10000
Zero Order Elimination
1000
100
10
1
0
1
logCt = logCo - Kel . t
2.303
2
3
4
5
6
Time
47
Plasma Concentration Profile after a
Single I.V. Injection
Plasma Concentration
Distribution and Elimination
10000
C0
Elimination only
1000
100
10
Distribution equilibrium
1
0
1
2
3
4
5
6
Time
48
Principle
Elimination of chemicals from the
body usually follows first order
kinetics with a characteristic halflife (t1/2) and fractional rate
constant (Kel).
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First Order Elimination
Clearance (CL): volume of plasma
cleared of chemical per unit time.
Clearance = Rate of elimination/plasma
conc.
Half-life of elimination (t 1/2): time
for plasma conc. to decrease by half.
Useful in estimating:
- time to reach steady state conc.
- time for plasma conc. to fall after
exposure stopped.
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Rate of elimination = Kel x Amount in body
= CL x Plasma Conc.
Therefore,
Kel x Amount = CL x Plasma Conc.
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 = 0.693 x Vd/CL
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Principle
The half-life of elimination of a chemical (and
its residence in the body) depends on its
clearance and its volume of distribution
t1/2 is proportional to Vd
t1/2 is inversely proportional to CL
t1/2 = 0.693 x Vd/CL
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Multiple dosing
On continuous steady administration of a chemical,
plasma concentration will rise fast at first then more
slowly and reach a plateau, where:
rate of input = rate of output
rate of administration = rate of elimination
ie. steady state is reached.
Therefore, at steady state:
Dose (Rate of Administration) = CL x plasma conc.
or steady state conc. = Dose/clearance
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Single dose
7
6
Toxic level
plasma conc
5
4
Cumulation
3
2
1
0
0
5
10
15
20
25
30
Time
54
55
The time to reach steady
state is ~4 t1/2’s
Concentration due to
repeated doses
Concentration due to a single dose
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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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Variability in Toxicokinetics
Plasma Drug
Concentration (mg/L)
60
50
40
30
20
10
0
0
5
10
15
Daily Dose (mg/kg)
58
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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