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Thedispositionofchemicalsenteringthebody(fromC.D.Klaassen,CasarettandDoullsToxicology,5th
ed.,NewYork:McGrawHill,1996).
LOCUS OF ACTION TISSUE
RECEPTORS RESERVOIRS
Bound Free Free Bound
SYSTEMIC
Bound Drug CIRCULATION
BIOTRANSFORMATION
Plasma concentration vs. time profile of a
single dose of a drug ingested orally
14
Plasma Concentration
12
10
8
6
4
2
0
0 5 10 15 20
TIME (hours)
12
Plasma Concentration
10 TOXIC RANGE
6 THERAPEUTIC RANGE
2 SUB-THERAPEUTIC
0
0 1 2 3 4 5 6 7 8 9
Dose
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%
to
Dose systemic
circulation
Examples of apparent Vds 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 d ru g s fro m th e b o d y
M K ID N E Y L IV E R
A
J f iltr a tio n m e ta b o lis m
O s e c r e tio n s e c r e tio n
R ( r e a b s o r p tio n )
M LU N G S O TH E R S
I
N e x h a la tio n m o t h e r 's m ilk
O s w e a t, s a liv a e tc .
R
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
Elimination by the Liver
Metabolism - major
1) Phase I and II reactions
Portal circulation
Gut
Elimination
14 DC/dt = kC
Plasma concentration
12 Ct = C0 . e Kel t
10 lnCt = lnC0 Kel t
8 logCt = logC0 Kel t
6 2.3
4
y = b a.x
2
0
0 5 10 15 20
TIME (hours)
Plasma Concentration 10000
100
10
1
0 1 2 3 4 5 6
Time
logCt = logC0 - Kel . t
2.303
Plasma Concentration Profile after
a Single I.V. Injection
lnCt = lnCo Kel.t
Vd = Dose/C0
t1/2 = 0.693/Kel
D
IN
O
LO
B
Blood Flow = Q
ELIMINATED
Rate of Elimination = QCA QCV = Q(CA-CV)
SIMILARLY FOR
Liver Clearance = Q(CA-CV)/CA = Q x EF OTHER ORGANS
Renal Clearance = UxV/Px
Therefore,
Kel x Amount = CL x Concentration
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 is proportional to Vd
t1/2 is inversely proportional to CL
6
Plasma Concentration
Therapeutic
5 level
3
Repeated doses
2
Maintenance dose
1
0
0 5 10 15 20 25 30
Time
The time to reach steady
state is ~4 t1/2s
Concentration due to
repeated doses
dC = CL x C x dt
60
Plasma concentration
50 i.v. route
40
30 oral route
20
10
0
0 2 4 6 8 10
Time (hours)
PENETRATION OF DRUG INTO THE EYE AFTER SYSTEMIC ADMINISTRATION
TRANSCORNEAL PENETRATION OF A DRUG AFTER TOPICAL
ADMINISTRATION
EPINEPHRINE