Pharmacokinetic Principles of Chemical Disposition

Site
Dosage Plasma Effects

of
Concen.
Action
Pharmacokinetic Pharmacodynamics
Toxicokinetics Toxicodynamics
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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).
Plasma concentration vs. time profile of a single
dose of a chemical ingested orally
Plasma Concentration
Time
12
10 TOXIC RANGE
6 THERAPEUTIC RANGE
2 SUB-THERAPEUTIC
0
0 1 2 3 4 5 6 7 8 9
Dose
LOCUS OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound
ABSORPTION Free Drug EXCRETION
SYSTEMIC
Bound Drug CIRCULATION
BIOTRANSFORMATION
Transfer of Chemicals across
Membranes
• Passive transport determined by:
PASSAGE ACROSS
- Permeability of surface
MEMBRANES
- Concentration gradient
- Surface area
• Permeability depends on:

Active
Passive For cell membranes:
- Lipid solubility
- pH of medium
- pK of chemical
Facilitated For endothelium
size, shape and charge of chemical
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)
pH = 2 pKa = 4.5 (a weak acid) pH = 7.4

0.1 = [ I ] [ I ] = 9990
100 = [ UI ] [ UI ] = 100
100.1 = total drug = 10090
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.
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 EFFECT
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
Absorption from the Lungs
REMOVAL OF
PARTICLES Absorption of Aerosols and
Particles:
1- Particle Size
Physical Lymph
2- Water solubility of the

chemical present in the
Phagocytosis aerosol or particle
DEPOSITION OF PARTICLES IN
THE RESPIRATORY SYSTEM
NasopharyngealR
egion
5-30 µm
Trachea
Bronchi
Bronchioles
1-5 µm
Alveolar Region
1 µm
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)
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
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

Bioavailability
Destroyed Not Destroyed Destroyed
in gut absorbed by gut wall by liver
Dose
to
systemic
circulation
Plasma concentration Bioavailability
70
60 i.v. route (AUC)o

50 (AUC)iv
40
30
oral route
20
10 Time (hours)
0
0 2 4 6 8 10
Principle
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.
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)
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
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
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
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
PRINCIPLE
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 body

= Vd
Concentration in Plasma
Volume of Distribution
Volume into which a drug appears to

distribute with a concentration equal to its
plasma concentration
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
Digoxin 7 490
E lim in a tio n
o f c h e m ic a ls fr o m th e b o d y
K ID N E Y L IV E R
f iltr a tio n m e ta b o lis m
s e c r e tio n e x c r e tio n
( r e a b s o r p t io n )
LU N G S O TH E R S
e x h a la tio n m o t h e r 's m i l k
s w e a t, s a liv a e tc .
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
Nephron Structure
The structure of the nephron (from A.C. Guyton, Textbook of Medical Physiology, Philadelphia, W.B. Saunders Co.; 1991
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
The enterohepatic shunt
Drug Liver
Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder
Portal circulation
Gut
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
CLINICAL
TOXICOKINETICS
Quantitative Aspects of
Toxicokinetics
Plasma Concentration 12
10 TOXIC RANGE
6 THERAPEUTIC RANGE
2 SUB-THERAPEUTIC
0
0 1 2 3 4 5 6 7 8 9
Dose
Influence of Variations in Relative Rates of Absorption
and Elimination on Plasma Concentration of an Orally
Administered Chemical
14
Plasma concentration
12
10
8
6
4
2
0
0 5 10 15 20
TIME (hours)
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. www.freelivedoctor.com
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 www.freelivedoctor.com DRUNKENNESS
First Order Elimination
14 dC/dt = k
12 Ct = Co e -Kel.t
10 lnCt = lnCo – Kel .t
8 logCt = logCo - Kel . t
6 2.303
4
y = b – a.x
2
0
0 5 10 15 20
TIME (hours)
Plasma Concentration 10000
Zero Order Elimination

1000
100
10
1
0 1 2 3 4 5 6
Time
logCt = logCo - Kel . t
2.303 www.freelivedoctor.com
Plasma Concentration Profile
after a Single I.V. Injection
Distribution and Elimination
10000
Elimination only
1000
C0
100
10
Distribution equilibrium
1
0 1 2 3 4 5 6
Time
lnCt = lnCo – Kel.t
Vd = Dose/C0
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.
lnCt = lnCo – Kel.t
t1/2 = 0.693/Kel
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.
Principle
Elimination of chemicals from
the body usually follows first
order kinetics with a
characteristic half-life (t1/2) and
fractional rate constant (Kel).
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.
Rate of elimination = Kel x Amount in body
Rate of elimination = CL x Plasma Concentration
Therefore,
Kel x Amount = CL x Concentration
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 =www.freelivedoctor.com
0.693 x Vd/CL
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

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.
or
steady state conc. = Dose/clearance
Single dose
7
6
Toxic level
5
plasma conc
3 Cumulation
2
0
0 5 10 15 20 25 30
Time
The time to reach steady
state is ~4 t1/2’s
Concentration due to
repeated doses
Concentration due to a single dose
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

dX/dt = CL x Conc.
dX = CL x Conc. x dt
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 AUCwww.freelivedoctor.com
and Dose x F = CL x AUC
Bioavailability = (AUC)o
70 (AUC)iv
60
50 i.v. route
40
30 oral route
20
10
0
0 2 4 6 8 10
Time (hours)
Variability in Pharmacokinetics
60
(Concentration (mg/L
50
Plasma Drug
40
30
20
10
0
0 5 10 15
(Daily Dose (mg/kg
PRINCIPLE
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.
THE DOSE-RESPONSE RELATIONSHIP
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed.,
New York: McGraw-Hill, 1996).

Pharmacokinetic Principles of Chemical Disposition

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Pharmacokinetic Principles of Chemical Disposition

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Site

Dosage Plasma Effects

ABSORPTION Free Drug EXCRETION

• Permeability depends on:

HA <==> H+ + A- B + H+ <==> BH+

pH = 2 pKa = 4.5 (a weak acid) pH = 7.4

100.1 = total drug = 10090

Intestinal vs. gastric absorption

2- Water solubility of the

Definition: the fraction of the administered

e.g. lidocaine bioavailability 35% due to

First Pass Effect

60 i.v. route (AUC)o

For chemicals taken by routes other than the i.v.

99.9 % bound 90.0

1 molecules free 100

Amount of drug in body

Volume into which a drug appears to

Bile Bile formation

• First order: rate of elimination proportional to

Rate of elimination = constant (CL) x

Zero Order Elimination

When t = 0, C = C0, i.e., the concentration at time

When Ct = ½ C0, then Kel.t = 0.693. This is the

t1/2 = 0.693 x Vd/CL

Concentration due to a single dose

• Plasma clearance Cl = Kel .Vd

• plasma half-life (t1/2) t1/2 = 0.693 / Kel

• Bioavailability (AUC)x / (AUC)iv

But Conc. x dt = small area under the curve. For total

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