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The Influence of Physicochemical
Properties on ADME
Iain Martin
Iain Martin; Physchem Forum 2
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Physchem and ADME
A quick tour of the influence of physicochemical
properties on:
Absorption
Distribution
Metabolism
Excretion
Iain Martin; Physchem Forum 2
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Absorption: solubility & permeability
• Aqueous solubility is a prerequisite for absorption
• Aqueous solubility and membrane permeability
tend to work in “opposite directions”
aq. solubility
permeability
• Therefore, a balance of physicochemical
properties is required to give optimal absorption
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Absorption: solubility & permeability
Lipinski (2000) J. Pharmacol. Toxicol. Meth., 44, p235
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Absorption: permeability
• Transcellular (Passive diffusion)
–
–
–
–
–
–
Concentration gradient (Fick’s law)
Lipid solubility
Degree of ionisation
Hydrogen bonding
Size/shape
………….
• Paracellular (passage through cell junctions
and aqueous channels)
• Active transport
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Permeability: Caco2 assay
2
y = -0.2183x 2 + 0.8639x + 0.4508
R2 = 0.5362
1.5
Riley et al., (2002)
Current Drug
Metabolism, 3, p527
Log Papp
1
0.5
0
-1
0
1
2
3
4
5
-0.5
clogD7.4
Strong relationship between permeability and logD
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Permeability: Caco2 assay
Papp
Neutral
Basic
LogP
• Issues of Solubility and membrane retention
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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
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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.
• Unionised form is more prevalent in the
small intestine.
• Although some absorption of acids takes
place in the stomach, absorption also
occurs in small intestine due to:
• Bases are well absorbed from small
intestine
• Very large surface area
• Very large surface area (600x cylinder)
• Removal of cpd by blood flow
• Removal of cpd by PPB & blood flow
• Ionisation equilibrium is countered by
distributional factors
• Ionisation of cpd in blood shifts
equilibrium in favour of absorption
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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
H
O
H
N
H
N
N
H
10
N
N
N
H
H
NH
N 2
H
NN
H
Iain Martin; Physchem Forum 2
H
H
O
H
O
N2
NH
O
N
N
H
H
H
O
H
H
H
H
H2N
N
N
H
H
Absorption: PSA
•
The hydrogen-bonding potential of a drug may be expressed as
“Polar Surface Area” (PSA)
•
Polar surface area is defined as a sum of surfaces of polar atoms
(usually oxygens, nitrogens) and their attached hydrogens
Distribution of Polar Surface Area
for orally administered CNS
(n=775) and non-CNS (n=1556)
drugs that have reached at least
Phase II efficacy trials. After Kelder et
250
non-CNS
Frequency
200
CNS
150
al., (1999) Pharmaceutical Research, 16, 1514
100
50
260
240
220
200
180
160
140
120
100
80
60
40
20
0
0
Polar Surface Area
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Oral drug properties
• Lipinski’s “Rule of 5”: Poor absorption is more
likely when:
• Log P is greater than 5,
• Molecular weight is greater than 500,
• There are more than 5 hydrogen bond donors,
• There are more than 10 hydrogen bond acceptors.
• Together, these parameters are descriptive of
solubility
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Oral drug properties
Molecular weight and lipophilicity
10
10
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
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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
Oral drug properties
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
• The number of rotatable bonds (molecular flexibility) may
also be important…………..
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Oral drug properties
95th (5th) percentile
Non-CNS
CNS
Mol. Wt.
611
449
PSA
127
73
HBA
9
5
HBD
5
3
Rot. Bond
14
9
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
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Are Leads different from Drugs?
•
Oprea et al., (2001). Property distribution analysis of leads and drugs.
•
Mean increase in properties going from Lead to Drug
∆MW
Mean
•
89
∆HAC
1.0
∆RTB
2.0
∆HDO ∆cLogP
0.2
1.16
∆cLogD
0.97
If, as a result of Lead “Optimisation”, our compounds become bigger
and more lipophilic, we need to make sure that we start from LeadLike properties rather than Drug-Like properties
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Distribution: Plasma and Tissue binding
• The extent of a drug’s distribution into a particular tissue
depends on its affinity for that tissue relative to
blood/plasma
• It can be thought of as “whole body chromatography” with
the tissues as the stationary phase and the blood as the
mobile phase
• Drugs which have high tissue affinity relative to plasma will
be “retained” in tissue (extensive distribution)
• Drugs which have high affinity for blood components will
have limited distribution
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Distribution: Plasma and Tissue binding
• The major plasma protein is albumin (35-50 g/L) which contains
lipophilic a.a. residues as well as being rich in lysine
• There is a trend of increasing binding to albumin with increasing
lipophilicity. In addition, acidic drugs tend to be more highly
bound due to charge-charge interaction with lysine
O
H
N
R1
R2
N
H
O
HA
H + + A+
NH3
• Bases also interact with alpha1-acid gp (0.4-1.0 g/L)
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Plasma and Tissue binding (pH 7.4)
• Tissue cell membranes contain negatively-charged
phospholipid
• Bases tend to have affinity for tissues due to charge-charge
interaction with phosphate head-group
• Acids tend not to have any tissue affinity due to chargecharge repulsion with phosphate head-group
+
R NH3
O
R
O
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Distribution - Vss
• What effect does plasma and tissue binding have on
the values of VSS that we observe?
VSS
fuP
= Vp + ( VT.
)
fu T
Vp = physiological volume of plasma
VT = physiological volume of tissue(s)
fup = fraction unbound in plasma
fuT = fraction unbound in tissue(s)
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Distribution - Vss
VSS
• Acids tend to be highly plasma
protein bound; hence fuP is
small
• Acids therefore tend to have
low VSS (< 0.5 L/kg)
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Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss(L/kg)
(L/kg)
Vss
• Acids have low tissue affinity
due to charge repulsion; hence
fuT is large
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
• Neutrals have affinity for both
plasma protein and tissue
• Changes in logD tend to
result in similar changes (in
direction at least) to both fuP
and fuT
• Neutrals tend to have
moderate VSS (0.5 – 5 L/kg)
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Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss(L/kg)
(L/kg)
Vss
• Affinity for both is governed
by lipophilicity
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
• Bases have higher affinity for
tissue due to charge
attraction
• Bases tend to have high VSS
(>3 L/kg)
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Clinically-used
Clinically-usedDrugs
Drugs
100
100
Vss(L/kg)
(L/kg)
Vss
• fuP tends to be (much) larger
than fuT
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
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-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
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Distribution: Ion trapping
• Ion trapping can occur when a drug distributes between
physiological compartments of differing pH
• The equilibrium between ionised and unionised drug will
be different in each compartment
• Since only unionised drug can cross biological
membranes, a drug may be “trapped” in the compartment
in which the ionised form is more predominant
• Ion trapping is mainly a phenomenon of basic drugs since
they tend to distribute more extensively and………….
• The cytosolic pH of metabolically active organs tends to
be lower than that of plasma, typically pH 7.2
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Distribution: Ion trapping
• Ion trapping of a weak base pKa 8.5
Plasma
pH 7.4
7.4
B
92.6
BH+
Membrane
B
4.8
BH+ 95.2
Distribution
Distribution
Iain Martin; Physchem Forum 2
Cytosol
pH 7.2
27
Ion trapping: lysosomes
• Lysosomes are membrane-enclosed organelles
• Contain a range of hydrolytic enzymes
responsible for autophagic and heterophagic
digestion
• Abundant in Lung, Liver, kidney, spleen with
smaller quantities in brain, muscle
• pH maintained at ~5 (4.8).
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Ion trapping: lysosomes
• Ion trapping of a weak base pH 8.5
Plasma
pH 7.4
7.4
92.6
Membrane
B
BH+
Cytosol
pH 7.2
B
4.8
BH+ 95.2
Distribution
Distribution
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Membrane
Lysosome
pH 4.8
B
0.02
BH+ 99.8
Ion trapping: lysosomes
OH
•
•
•
•
Effect of lysosomal uptake is
more profound for dibasics
HO
O
O
O
O
HO
HO
OO
Theoretical lysosome:plasma
ratio of ~ 160,000
N
O
HO
O
Erythromycin VSS = 0.5 L/kg
Apparent volume of liver may
be 1000 X physical volume
N
Azithromycin achieves in vivo
tissue: plasma ratios of up to
100-fold and is found
predominantly in lysosome-rich
tissues
OH
HO
OH
N
HO
O
O
O
O
O
O
O
OH
Azithromycin VSS = 28 L/kg
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Salicylate poisoning
O
O
OH
OH
OH
O
O
•
Aspirin (acetylsalicylic acid) is metabolised to the active component
– salicylic acid
•
Due to its acidic nature and extensive ionisation, salicylate does not
readily distribute into tissues
•
But after an overdose, sufficient salicylate enters the CNS to
stimulate the respiratory centre, promoting a reduction in blood CO2
•
The loss of blood CO2 leads a rise in blood pH - respiratory
alkalosis
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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…………
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Salicylate poisoning
1
pH 7.4
OH
OH
OH
O
O
O
4
pH 6.8
8000
Bicarbonate
BRAIN
Normal
8000
BLOOD
Acidosis
• Acidosis leads to increase in unionised salicylate in the blood,
promoting distribution into brain resulting in CNS toxicity.
• This is treated with bicarbonate which increases blood pH and
promotes redistribution out of the CNS.
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Salicylate poisoning
KIDNEY
BLOOD
Reabsorption
O
Unbound fraction of both
species is filtered; Only
neutral species is reabsorbed
pH 6.0
OH
OH
OH
1
O
Filtration
OH
O
O
Reabsorption
0.01
300
Bicarbonate
OH
URINE
pH 8.0
OH
O
O
300
• Bicarbonate incrseases urine pH leading to significantly
decreased reabsorption and hence increased excretion
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Metabolism: lipophilicity
OH
X
N
Metabolic stability
N
OH
NH
OGluc
N
-1
0
1
2
3
4
logD
As a general rule, liability to metabolism increases with increasing
lipophilicity. However, the presence of certain functional groups and
SAR of the metabolising enzymes is of high importance
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Metabolism vs. Excretion
• Effect of logD on renal and metabolic clearance for a
series of chromone-2-carboxylic acids
16
Clearance (ml/min/kg)
Replotted from Smith et al.,
(1985) Drug Metabolism
Reviews, 16, p365
Renal
14
Metabolic
12
10
8
6
4
2
0
-1
-0.5
0
0.5
1
1.5
2
LogD
• Balance between renal elimination into an aqueous
environment and reabsorption through a lipophilic membrane
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Renal Excretion
• Effect of LogD on renal clearance of β-blockers
Van de Waterbeemd et al.,
(2001) J. Med. Chem, 44, p1313
• Note that only unbound drug is filtered and that PPB
increases with logD
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Summary
•
ADME processes are determined by the interaction of drug molecules
with:
– Lipid membranes
– Plasma and tissue proteins
– Drug metabolising enzymes
– Transporters
•
These interactions are governed, to a large extent, by the
physicochemical properties of the drug molecules
Understanding the influence of these properties is therefore pivotal to
understanding ADME and can lead to predictive models
In general, good (oral) ADME properties requires a balance of
physicochemical properties
Lead Optimisation needs “physicochemical room” to optimise
•
•
•
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References & Further Reading
•
MacIntyre and Cutler (1988). The potential role of lysosomes in the tissue
distribution of weak bases. Biopharmaceutics and Drug Disposition, 9, 513526
•
Proudfoot (2005). The evolution of synthetic oral drug properties.
Bioorganic and Medicinal Chemistry Letters 15, 1087-1090
•
Oprea et al., (2001) J. Chem. Inf. Comput. Sci. 41, 1308-1315
•
van de Waterbeemd et al., (2001). Lipophilicity in PK design: methyl, ethyl,
futile. Journal of Computer-Aided Molecular Design. 15, 273-86
•
Wenlock et al., (2003). A comparison of physiochemical property profiles of
development and marketed oral drugs. J. Med. Chem. 2003
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