PK

The Influence of Physicochemical
Properties on ADME
Iain Martin
Iain Martin; Physchem Forum 2
Physchem and ADME

A quick tour of the influence of physicochemical
properties on:
Absorption
Distribution
Metabolism
Excretion
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
Absorption: solubility & permeability
Lipinski (2000) J. Pharmacol. Toxicol. Meth., 44, p235
Absorption: permeability
Transcellular (Passive diffusion)
Concentration gradient (Ficks law)

Lipid solubility
Degree of ionisation
Hydrogen bonding
Size/shape
.
Paracellular (passage through cell junctions

and aqueous channels)
Active transport
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
0.5
0
-1
-0.5
clogD7.4
Strong relationship between permeability and logD

Permeability: Caco2 assay
Papp
Neutral
Basic
LogP
Issues of Solubility and membrane retention

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
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
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
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
Polar Surface Area

11
Oral drug properties

Lipinskis 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
12

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
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
The number of rotatable bonds (molecular flexibility) may

also be important..
14

95th (5th) percentile
Non-CNS
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
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
16
Distribution: Plasma and Tissue binding

The extent of a drugs 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
17
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)

18
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
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
Vp = physiological volume of plasma

VT = physiological volume of tissue(s)
fup = fraction unbound in plasma
fuT = fraction unbound in tissue(s)
20
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)
21
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)
22
Clinically-used
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)
23
Clinically-used
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
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
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
26
Distribution: Ion trapping

Ion trapping of a weak base pKa 8.5
Plasma
pH 7.4
7.4
92.6
BH+
Membrane
4.8
BH+ 95.2
Distribution
Distribution
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).
28

Ion trapping of a weak base pH 8.5
Plasma
pH 7.4
7.4
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

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
HO
O
Erythromycin VSS = 0.5 L/kg
Apparent volume of liver may

be 1000 X physical volume
Azithromycin achieves in vivo

tissue: plasma ratios of up to
100-fold and is found
predominantly in lysosome-rich
tissues
OH
HO
OH
HO
O
O
O
O
O
OH
Azithromycin VSS = 28 L/kg

30
Salicylate poisoning
O
O
OH
OH
OH
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
31
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
1
pH 7.4
OH
OH
OH
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.
33
KIDNEY
BLOOD
Reabsorption
Unbound fraction of both

species is filtered; Only
neutral species is reabsorbed
pH 6.0
OH
OH
OH
Filtration
OH
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
34
Metabolism: lipophilicity
OH
X
Metabolic stability
OH
NH
OGluc
N
-1
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
35
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
0.5
1.5
LogD
Balance between renal elimination into an aqueous

environment and reabsorption through a lipophilic membrane
36
Renal Excretion
Effect of LogD on renal clearance of -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
37
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
38
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
39

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The Influence of Physicochemical

Iain Martin; Physchem Forum 2

Physchem and ADME

Iain Martin; Physchem Forum 2

Absorption: solubility & permeability

Therefore, a balance of physicochemical

Absorption: solubility & permeability

Lipinski (2000) J. Pharmacol. Toxicol. Meth., 44, p235

Iain Martin; Physchem Forum 2

Concentration gradient (Ficks law)

Paracellular (passage through cell junctions

Permeability: Caco2 assay

Riley et al., (2002)

Strong relationship between permeability and logD

Permeability: Caco2 assay

Issues of Solubility and membrane retention

Unionised form is more prevalent in the

Although some absorption of acids takes

Bases are well absorbed from small

Very large surface area (600x cylinder)

Removal of cpd by blood flow

Removal of cpd by PPB & blood flow

Ionisation equilibrium is countered by

Ionisation of cpd in blood shifts

Iain Martin; Physchem Forum 2

Iain Martin; Physchem Forum 2

The hydrogen-bonding potential of a drug may be expressed as

Polar surface area is defined as a sum of surfaces of polar atoms

al., (1999) Pharmaceutical Research, 16, 1514

Polar Surface Area

Oral drug properties

Together, these parameters are descriptive of

Oral drug properties

Iain Martin; Physchem Forum 2

Oral drug properties

The number of rotatable bonds (molecular flexibility) may

Oral drug properties

Iain Martin; Physchem Forum 2

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

If, as a result of Lead Optimisation, our compounds become bigger

Iain Martin; Physchem Forum 2

Distribution: Plasma and Tissue binding

Iain Martin; Physchem Forum 2

Distribution: Plasma and Tissue binding

Bases also interact with alpha1-acid gp (0.4-1.0 g/L)

Plasma and Tissue binding (pH 7.4)

Iain Martin; Physchem Forum 2

Vp = physiological volume of plasma

Iain Martin; Physchem Forum 2

Acids tend to be highly plasma

Acids therefore tend to have

Iain Martin; Physchem Forum 2

Acids have low tissue affinity

Neutrals have affinity for both

Changes in logD tend to

Affinity for both is governed

Bases have higher affinity for

Bases tend to have high VSS

Iain Martin; Physchem Forum 2

fuP tends to be (much) larger

Iain Martin; Physchem Forum 2

Iain Martin; Physchem Forum 2