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Properties on ADME
Iain Martin
Absorption: permeability
Transcellular (Passive diffusion)
Log Papp
0.5
0
-1
-0.5
clogD7.4
Papp
Neutral
Basic
LogP
Absorption - ionisation
The central principle is that only unionised (neutral) form
of drugs will cross a membrane
Gut lumen
H + + A-
Blood stream
HA
H+ + A-
HA
Blood flow
Absorption
Absorption
Iain Martin; Physchem Forum 2
Absorption - ionisation
In man, stomach is ~ pH 2 and small intestine ~ pH 6
(weak) BASES
(weak) ACIDS
Unionised form is more prevalent in the
stomach.
Absorption H-bonding
Diffusion through a lipid membrane is facilitated by shedding
H-bonded water molecules
The higher the H-bonding capacity, the more energeticallyunfavourable this becomes
H
H
O
H
N
N
H
N
10
N
N
NH
N 2
NN
N2
NH
H
H2N
N
Absorption: PSA
250
non-CNS
Frequency
200
CNS
150
100
50
260
240
220
200
180
160
140
120
100
80
60
40
20
11
12
20
20
15
15
pdr99
pdr99
10
10
55
00
55
PDR99
PDR99
00
100
100 200
200 300
300 400
400 500
500 600
600 700
700 800
800 900
900
-5
-5
Mwt
Mwt
count %
%
count
count %
%
count
25
25
-2.5
-2.5
00
2.5
2.5
55
ACDlogP
ACDlogP
13
7.5
7.5
10
10
35
35
40
40
35
35
30
30
25
25
20
20
15
15
10
10
55
00
30
30
PDR99
PDR99
count %
%
count
count %
%
count
Hydrogen bonding
25
25
20
20
PDR99
PDR99
15
15
10
10
55
00
44
88
12
12
16
16
00
20
20
00
Acceptors
Acceptors
22
44
66
88
10
10
Donors
Donors
14
CNS
Mol. Wt.
611
449
PSA
127
73
HBA
HBD
Rot. Bond
14
6.2 (-1.2)
5.7 (0.4)
cLogP
In general, CNS drugs are smaller, have less rotatable bonds and
occupy a narrower range of lipophilicities. They are also
characterised by lower H-bonding capacity
15
MW
Mean
89
HAC
1.0
RTB
2.0
HDO cLogP
0.2
1.16
cLogD
0.97
16
17
R1
R2
N
H
O
HA
H + + A+
NH3
18
R NH3
O
R
19
Distribution - Vss
What effect does plasma and tissue binding have on
the values of VSS that we observe?
VSS
fuP
= Vp + ( VT.
)
fu T
20
Distribution - Vss
VSS
21
Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss(L/kg)
(L/kg)
Vss
fuP
= Vp + ( VT.
)
fuT
Acid
Acid
10
10
11
0.1
0.1
0.01
0.01
-2-2 -1-1
00
11 22
LogD
LogD
33
44
55
Distribution - Vss
VSS
22
Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss(L/kg)
(L/kg)
Vss
fuP
= Vp + ( VT.
)
fuT
Neutral
Neutral
10
10
11
0.1
0.1
0.01
0.01
-2-2 -1-1
00
11 22
LogD
LogD
33
44
55
Distribution - Vss
VSS
23
Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss(L/kg)
(L/kg)
Vss
fuP
= Vp + ( VT.
)
fuT
Base
Base
10
10
11
0.1
0.1
-2-2 -1-1 00
11 22
LogD
LogD
33
44
55
Distribution - Vss
VSS
fuP
= Vp + ( VT.
)
fuT
Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss (L/kg)
Vss (L/kg)
10
10
Acid
Acid
Base
Base
Neutral
Neutral
11
0.1
0.1
0.01
0.01
-2-2
-1-1
00
24
11
22
LogD
LogD
33
44
55
Distribution effect of pH
Distribution
Ion trapping of basic compounds
Distribution/Excretion
Aspirin overdose & salicylate poisoning
25
26
92.6
BH+
Membrane
4.8
BH+ 95.2
Distribution
Distribution
Cytosol
pH 7.2
27
28
92.6
Membrane
BH+
Cytosol
pH 7.2
4.8
BH+ 95.2
Distribution
Distribution
29
Membrane
Lysosome
pH 4.8
0.02
BH+ 99.8
HO
O
O
O
O
HO
HO
OO
Theoretical lysosome:plasma
ratio of ~ 160,000
HO
O
OH
HO
OH
HO
O
O
O
O
O
OH
30
Salicylate poisoning
O
O
OH
OH
OH
Due to its acidic nature and extensive ionisation, salicylate does not
readily distribute into tissues
31
Salicylate poisoning
The body responds to the alkalosis by excreting
bicarbonate to reduce blood pH back to normal
In mild cases, blood pH returns to normal. However in
severe cases (and in children) blood pH can drop too far
leading to metabolic acidosis
This has further implications on the distribution of
salicylate, its toxicity and subsequent treatment
32
Salicylate poisoning
1
pH 7.4
OH
OH
OH
pH 6.8
8000
Bicarbonate
BRAIN
Normal
8000
BLOOD
Acidosis
33
Salicylate poisoning
KIDNEY
BLOOD
Reabsorption
pH 6.0
OH
OH
OH
Filtration
OH
O
Reabsorption
0.01
300
Bicarbonate
OH
URINE
pH 8.0
OH
O
O
300
34
Metabolism: lipophilicity
OH
X
Metabolic stability
OH
NH
OGluc
N
-1
logD
35
Clearance (ml/min/kg)
Renal
14
Metabolic
12
10
8
6
4
2
0
-1
-0.5
0.5
1.5
LogD
36
Renal Excretion
Effect of LogD on renal clearance of -blockers
Van de Waterbeemd et al.,
(2001) J. Med. Chem, 44, p1313
37
Summary
38
MacIntyre and Cutler (1988). The potential role of lysosomes in the tissue
distribution of weak bases. Biopharmaceutics and Drug Disposition, 9, 513526
39