3. DISPOSITION OF DRUGS
The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th
ed., New York: McGraw-Hill, 1996).
4. Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”
TISSUE
RESERVOIRS
SYSTEMIC
CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATION
5. Plasma concentration vs. time profile of a
single dose of a drug ingested orally
0
2
4
6
8
10
12
14
0 5 10 15 20
TIME (hours)
Plasma
Concentration
7. Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”
TISSUE
RESERVOIRS
SYSTEMIC
CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATION
8. 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
10. PRINCIPLE
PRINCIPLE
For drugs taken by routes other than the
i.v. route, the extent of absorption and
the bioavailability must be understood in
order to determine what dose will induce
the desired therapeutic effect. It will also
explain why the same dose may cause a
therapeutic effect by one route but a
toxic or no effect by another.
11. Drugs appear to distribute in the body as if it
were a single compartment. The magnitude of
the drug’s distribution is given by the apparent
volume of distribution (Vd).
Vd = Amount of drug in body ÷ Concentration in Plasma
PRINCIPLE
PRINCIPLE
(Apparent) Volume of Distribution:
Volume into which a drug appears to distribute with
a concentration equal to its plasma concentration
13. 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
15. 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
16. 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
17. The enterohepatic shunt
Portal circulation
Liver
gall bladder
Gut
Bile
duct
Drug
Biotransformation;
glucuronide
produced
Bile formation
Hydrolysis by
beta glucuronidase
19. 0
2
4
6
8
10
12
14
0 5 10 15 20
TIME (hours)
Plasma
concentration
Influence of Variations in Relative Rates of
Absorption and Elimination on Plasma
Concentration of an Orally Administered Drug
Ka/Ke=10
Ka/Ke=0.1
Ka/Ke=0.01
Ka/Ke=1
20. 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 ∝ Amount
Rate of elimination = K x Amount
21. Zero Order Elimination
Pharmacokinetics of Ethanol
• Ethanol is distributed in total body water.
• Mild intoxication at 1 mg/ml in plasma.
• How much should be ingested to reach it?
Answer: 42 g or 56 ml of pure ethanol (VdxC)
Or 120 ml of a strong alcoholic drink like whiskey
• Ethanol has a constant elimination rate = 10 ml/h
• 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 DRUNKENNES Coma Death
22. 0
2
4
6
8
10
12
14
0 5 10 15 20
TIME (hours)
Plasma
concentration
Ct = C0 . e – Kel •t
lnCt = lnC0 – Kel • t
logCt = logC0 – Kel •t
2.3
DC/dt = – k•C
y = b – a.x
First Order Elimination
dA/dt A
∝ DA/dt = – k•A
24. Time
P
la
sm
a
C
o
nc
e
ntra
tio
n
0 1 2 3 4 5 6
1
10
100
1000
10000
C0
Distribution equilibrium
Elimination only
Distribution and Elimination
Plasma Concentration Profile
after a Single I.V. Injection
25. 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
26. lnCt = lnC0 – 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
27. PRINCIPLE
PRINCIPLE
Elimination of drugs from the
body usually follows first order
kinetics with a characteristic
half-life (t1/2) and fractional rate
constant (Kel).
28. First Order Elimination
• Clearance: volume of plasma cleared of drug
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
concentration to fall after dosing is stopped.
29. IN
OUT
Blood Flow = Q
CA CV
BLOOD
B
L
O
O
D
ELIMINATED
Rate of Elimination = QCA – QCV = Q(CA-CV)
Liver Clearance = Q(CA-CV)/CA = Q x EF
SIMILARLY FOR
OTHER ORGANS
Renal Clearance = Ux•V/Px
Total Body Clearance = CLliver + CLkidney + CLlungs + CLx
•
30. 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 = 0.693 x Vd/CL
31. PRINCIPLE
PRINCIPLE
The half-life of elimination of a drug (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
32. Multiple dosing
• On continuous steady administration of a drug, 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
If you aim at a target plasma level and you know the
clearance, you can calculate the dose required.
35. Concentration due to a single dose
Concentration due to
repeated doses
The time to reach steady
state is ~4 t1/2’s
36. Pharmacokinetic parameters
• Volume of distribution Vd = DOSE / C0
• Plasma clearance Cl = Kel .Vd
• plasma half-life t1/2= 0.693 / Kel
• Bioavailability (AUC)x / (AUC)iv
Get equation of regression line; from it get Kel, C0 , and AUC
37. But C x dt = small area under the curve. For total
amount eliminated (which is the 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
dC/dt = CL x C
dC = CL x C x dt
40. PRINCIPLE
PRINCIPLE
The absorption, distribution and
elimination of a drug are qualitatively
similar in all individuals. However, for
several reasons, the quantitative aspects
may differ considerably. Each person
must be considered individually and
doses adjusted accordingly.
