toxicokinetics
TRANSCRIPT
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Dosage EffectsSiteof
Action
PlasmaConcen.
PharmacokineticToxicokinetics
PharmacodynamicsToxicodynamics
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DISPOSITION OF CHEMICALS
The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
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Pla
sma
Con
cen
trat
ion
Time
Plasma concentration vs. time profile of a single dose of a chemical ingested orally
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Dose
Pla
sma
Co
nce
ntr
atio
n
0 1 2 3 4 5 6 7 8 90
2
4
6
8
10
12
TOXIC RANGE
THERAPEUTIC RANGE
SUB-THERAPEUTIC
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Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”TISSUE
RESERVOIRS
SYSTEMIC CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATIONwww.freelivedoctor.com
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Transfer of Chemicals across Membranes
• 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
PASSAGE ACROSS MEMBRANES
Passive
Facilitated
Active
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Weak Acids and Weak Bases
HA <==> H+ + A- B + H+ <==> BH+
[ UI ] [ I ] [ UI ] [ I ]
pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)
pKa = 4.5 (a weak acid)
100 = [ UI ] [ UI ] = 100
pH = 2 pH = 7.40.1 = [ I ] [ I ] = 9990
100.1 = total drug = 10090
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Factors Affecting Absorption (G.I., lungs, skin)
• Determinants of Passive Transfer (lipid solubility, pH, pK, area, concentration gradient).
• Blood flow to site.
• Dissolution in the acqueous medium surrounding the absorbing surface.
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Factors Affecting Absorption from the GI Tract
• Disintegration of dosage form and dissolution of particles
• Chemical stability of chemical in gastric and intestinal juices and enzymes
• Motility and mixing in GI tract• Presence and type of food• Rate of gastric emptying
Intestinal vs. gastric absorption
FIRST PASS EFFECTwww.freelivedoctor.com
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Absorption from the Lungs
• 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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Absorption of Aerosols and Particles:
1- Particle Size
2- Water solubility of the chemical present in the aerosol or particle
REMOVAL OFPARTICLES
Physical
Phagocytosis
Lymph
Absorption from the Lungs
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NasopharyngealRegion
5-30 µm
Trachea
Bronchi
Bronchioles
1-5 µm
Alveolar Region
1 µm
DEPOSITION OF PARTICLES IN THE RESPIRATORY SYSTEM
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Absorption from the Skin
• 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 www.freelivedoctor.com
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Bioavailability
Dose
Destroyed in gut
Notabsorbed
Destroyed by gut wall
Destroyedby liver
tosystemiccirculation
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0
10
20
30
40
50
60
70
0 2 4 6 8 10
Plasma concentration
Time (hours)
i.v. route
oral route
Bioavailability
(AUC)o
(AUC)iv
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PrinciplePrinciple
For chemicals taken by routes other than the i.v. route, 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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• 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)
Distribution into body compartments
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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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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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100-fold increase in free pharmacologically active concentration at site of action.
NON-TOXIC TOXIC
Alter plasma binding of chemicals
1000 molecules
% bound
molecules free
99.9 90.0
100 1
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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).
Amount of drug in bodyConcentration in Plasma
Vd =
PRINCIPLEPRINCIPLE
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Volume of Distribution
Volume into which a drug appears to distribute with a concentration equal to its plasma concentration
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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
Digoxin 7 490
Examples of apparent Vd’s for some drugs
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KID N EYf iltra tion
secretion(reab sorp tion )
LIVERm etabolism
excretion
LU N GSexhalation
OTH ER Sm other's m ilk
sw eat, sa liva etc .
Elim inationof chem icals from the body
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Elimination by the Kidney• Excretion - major
1) glomerular filtrationglomerular 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
The structure of the nephron (from A.C. Guyton, Textbook of Medical Physiology, Philadelphia, W.B. Saunders Co.; 1991www.freelivedoctor.com
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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
Portal circulation
Liver
gall bladder
Gut
Bile
duct
Drug
Biotransformation;glucuronide produced
Bile formation
Hydrolysis bybeta glucuronidase
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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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CLINICAL TOXICOKINETICS
Quantitative Aspects of Toxicokinetics
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Dose
Pla
sma
Co
nce
ntr
atio
n
0 1 2 3 4 5 6 7 8 90
2
4
6
8
10
12
TOXIC RANGE
THERAPEUTIC RANGE
SUB-THERAPEUTIC
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0
2
4
6
8
10
12
14
0 5 10 15 20
TIME (hours)
Pla
sma
con
cen
trat
ion
Influence of Variations in Relative Rates of Absorption and Elimination on Plasma
Concentration of an Orally Administered Chemical
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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 Pharmacokinetics 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.
RARELY DONE
DRUNKENNESS
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0
2
4
6
8
10
12
14
0 5 10 15 20
TIME (hours)
Pla
sma
conc
entr
atio
n
Ct = Co e-Kel.t
lnCt = lnCo – Kel .t
logCt = logCo - Kel . t 2.303
dC/dt = k
y = b – a.x
First Order Elimination
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Time
Pla
sma
Co
nce
ntr
atio
n
0 1 2 3 4 5 61
10
100
1000
10000
Zero Order Elimination
logCt = logCo - Kel . t 2.303
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Time
Plasma Concentration
0 1 2 3 4 5 61
10
100
1000
10000
C0
Distribution equilibrium
Elimination only
Distribution and Elimination
Plasma Concentration Profile after a Single I.V. Injection
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lnCt = lnCo – Kel.t
When t = 0, C = C0, i.e., the concentration at time zero when distribution is complete and
elimination has not started yet. Use this value and the dose to calculate Vd.
Vd = Dose/C0
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lnCt = lnCo – Kel.t
When Ct = ½ C0, then Kel.t = 0.693. This is the time for the plasma concentration to reach half
the original, i.e., the half-life of elimination.
t1/2 = 0.693/Kel
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PrinciplePrinciple
Elimination of chemicals from the body usually follows first
order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).
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First Order Elimination
• Clearance: volume of plasma cleared of chemical per unit time.Clearance = Rate of elimination/plasma conc.
• Half-life of elimination: time for plasma conc. to decrease by half.
Useful in estimating: - time to reach steady state
concentration. - time for plasma conc. to fall after exposure stopped.
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Rate of elimination = Kel x Amount in bodyRate of elimination = CL x Plasma Concentration
Therefore,Kel x Amount = CL x Concentration
Kel = CL/Vd
0.693/t1/2 = CL/Vd
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PrinciplePrinciple
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 administration = rate of elimination ie. steady state is reached.
• Therefore, at steady state:Dose (Rate of Administration) = clearance x plasma conc.
orsteady state conc. = Dose/clearance
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0
1
2
3
4
5
6
7
0 5 10 15 20 25 30
Time
pla
sma
con
c
Cumulation
Toxic level
Single dose
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Concentration due to a single dose
Concentration due to repeated doses
The time to reach steady state is ~4 t1/2’s
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Pharmacokinetic 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 (AUC)x / (AUC)iv
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But Conc. x dt = small area under the curve. For total amount eliminated (which is total given or the
dose if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC
dX/dt = CL x Conc.
dX = CL x Conc. x dt
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0
10
20
30
40
50
60
70
0 2 4 6 8 10
Pla
sma
con
cen
trat
ion
Time (hours)
Bioavailability (AUC)o
(AUC)iv=
i.v. route
oral route
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Daily Dose (mg/kg)
Pla
sma
Dru
gC
on
cen
trat
ion
(m
g/L
)
0 5 10 150
10
20
30
40
50
60
Variability in Pharmacokinetics
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PRINCIPLEPRINCIPLE
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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THE DOSE-RESPONSE RELATIONSHIP
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
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