Download Absorption, distribution, metabolism and excretion

Learning objectives
• To know what data is available from pharmacokinetic
studies in man and how to handle it
• To know how to calculate the basic pharmacokinetic
parameters of clearance, t(half); volume of distribution,
bioavailability; Kel
• To understand the implications of these parameters for
satisfactory therapy and the construction of suitable
dosage regimens for patients
• To know how knowledge of pharmacokinetic parameters
can be exploited in drug design and formulation
development.
Pharmacokinetics
• Study of ADME on a quantitative basis
In man study blood, urine, faeces, expired air.
Measure urine volume & concentration of drug
conc in urine x vol per min = RENAL
plasma concentration
CLEARANCE
If neither secreted nor reabsorbed then clearance =
clearance of inulin = 120 ml/min
If completely cleared by secretion then clearance =
clearance of p-hippuric acid = renal blood flow = 700
ml/min
Plasma concentration
14
Ct = Co e-tKel
lnCt = lnCo - Kel t
12
10
logCt = logCo - Kel . t
2.303
8
6
y
4
=
c
m
x
2
0
0
5
10
TIME (hours)
15
20
Bioavailability
Plasma concentration
60
i.v. route
50
(AUC)o / (AUC)iv
40
30
oral route
20
Time (hours)
10
0
0
2
4
6
8
=1.5; antilog 1.5 = 31.6
1.6
logCt = logCo - Kel . t
2.303
1.1
0.6
TIME (hours)
0.1
0
5
-0.4
-0.9
log plasma
concentration
10
15
20
Pharmacokinetic parameters
• Volume of distribution
V = DOSE / Co
• Plasma clearance
Cl = Kel .V
• plasma half-life (t1/2)
or
directly from graph
t1/2 = 0.693 / Kel
• Bioavailability
(AUC)x / (AUC)iv
Multiple dosing
• On multiple dosing plasma concentration will rise and
fall with each dose andwill increase until
administration = elimination
ie. steady state is reached.
• At steady state hourly dose rate (D=dose; T=interval
between doses in hours)
D/T = clearance x plasma conc
or steady state conc = D/(T x clearance)
• At each dose the level will oscillate through D/V
plasma conc
toxic
6
5
4
effective
Cumulation and use of
loading doses
3
2
1
Time
0
0
5
10
15
20
25