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The Influence of Physicochemical
Properties on ADME
Iain Martin
Iain Martin; Physchem Forum 2
1
Physchem and ADME
A quick tour of the influence of physicochemical
properties on:
Absorption
Distribution
Metabolism
Excretion
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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 = -0.2183x2 + 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
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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
H
• The higher the H-bonding capacity, the more energeticallyunfavourable this becomes
N
N
NN
N
H
Iain Martin; Physchem Forum 2
N2
NH
NH
N2
H
H
H
H
H
H
N
O
H
H2N
N
N
H
N
N
N
N
H
H
10
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
250
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
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
20
15
pdr99
10
5
count %
count %
25
5
PDR99
0
0
100 200 300 400 500 600 700 800 900
-5
Mwt
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-2.5
0
2.5
5
ACDlogP
13
7.5
10
Oral drug properties
35
40
35
30
25
20
15
10
5
0
30
PDR99
count %
count %
Hydrogen bonding
25
20
PDR99
15
10
5
0
4
8
12
16
0
20
0
Acceptors
2
4
6
8
10
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
ΔMW
Mean
89
ΔHAC
1.0
ΔRTB
2.0
ΔHDO ΔcLogP
0.2
1.16
ΔcLogD
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
fu P
 Vp  ( VT.
)
fuT
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  Vp  ( VT.
• 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 Drugs
100
Acid
Vss (L/kg)
• Acids have low tissue affinity
due to charge repulsion; hence
fuT is large
fu P
)
fuT
10
1
0.1
0.01
-2
-1
0
1
2
LogD
3
4
5
Distribution - Vss
VSS  Vp  ( VT.
• 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 Drugs
100
Vss (L/kg)
• Affinity for both is governed
by lipophilicity
fu P
)
fuT
Neutral
10
1
0.1
0.01
-2
-1
0
1
2
LogD
3
4
5
Distribution - Vss
VSS  Vp  ( VT.
• Bases have higher affinity for
tissue due to charge
attraction
• Bases tend to have high VSS
(>3 L/kg)
Clinically-used Drugs
100
Base
Vss (L/kg)
• fuP tends to be (much) larger
than fuT
10
1
0.1
-2
-1
0
1
2
LogD
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fu P
)
fuT
3
4
5
Distribution - Vss
VSS  Vp  ( VT.
Clinically-used Drugs
100
Acid
Base
Neutral
Vss (L/kg)
10
1
0.1
0.01
-2
-1
0
1
LogD
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2
3
4
5
fu P
)
fuT
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
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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
B
92.6
BH+
Membrane
Cytosol
pH 7.2
B
4.8
BH+ 95.2
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
O
N
HO
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 b-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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