The Influence of Physicochemical Drugs On ADME, Iain Martin PDF

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

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 (Fick’s law)
– Lipid solubility
– Degree of ionisation
– Hydrogen bonding
– Size/shape
– ………….
• Paracellular (passage through cell junctions
and aqueous channels)
• Active transport
Permeability: Caco2 assay
2
Riley et al., (2002)
y = -0.2183x 2 + 0.8639x + 0.4508 Current Drug
R2 = 0.5362
1.5 Metabolism, 3, p527
1
Log Papp
0.5
0
-1 0 1 2 3 4 5
-0.5
clogD7.4
Strong relationship between permeability and logD

Permeability: Caco2 assay
Neutral
Basic
Papp
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 Blood stream
H + + A- HA HA H+ + A-
Blood flow
Absorption
Absorption
Absorption - ionisation
• In man, stomach is ~ pH 2 and small intestine ~ pH 6
(weak) ACIDS (weak) BASES

• Unionised form is more prevalent in the • Unionised form is more prevalent in the
stomach. small intestine.
• Although some absorption of acids takes • Bases are well absorbed from small
place in the stomach, absorption also intestine
occurs in small intestine due to: • 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
• Ionisation of cpd in blood shifts distributional factors
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 energetically-
unfavourable this becomes
H H
H
O H O
H
H H H H
O
O
H2N
N N N
N N2
NH N N N N
H H H H
H
NN N
H
N N
NH
N 2
H H N
H
O H H
O
H
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
non-CNS for orally administered CNS
200
CNS (n=775) and non-CNS (n=1556)
drugs that have reached at least
Frequency
150
Phase II efficacy trials. After Kelder et
al., (1999) Pharmaceutical Research, 16, 1514
100
50
0
0
20
40
60
80
100
120
140
160
180
200
220
240
260
Polar Surface Area

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
Molecular weight and lipophilicity

25 10
10
25
20
20
%
count %
%
count %
15
15
count
pdr99
count
pdr99 55 PDR99
PDR99
10
10
55
00
00
100
100 200
200 300
300 400
400 500
500 600
600 700
700 800
800 900
900 -5
-5 -2.5
-2.5 00 2.5
2.5 55 7.5
7.5 10
10
Mwt
Mwt ACDlogP
ACDlogP

Hydrogen bonding
35
35
40
40
35
35 30
30
30
30 25
%
25
count %
%
25
count %
25 20
20
count
PDR99
count
20
20 PDR99 PDR99
PDR99
15
15 15
15
10
10 10
10
55
55
00
00
00 44 88 12
12 16
16 20
20 00 22 44 66 88 10
10
Acceptors
Acceptors Donors
Donors
• The number of rotatable bonds (molecular flexibility) may

also be important…………..
95th (5th) percentile
Non-CNS CNS
Mol. Wt. 611 449
PSA 127 73
HBA 9 5
HBD 5 3
Rot. Bond 14 9
cLogP 6.2 (-1.2) 5.7 (0.4)
• 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

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 ∆HAC ∆RTB ∆HDO ∆cLogP ∆cLogD
Mean 89 1.0 2.0 0.2 1.16 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 Lead-
Like properties rather than Drug-Like properties

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

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 R2
R1 N
N
H
O
HA H + + A-
+
NH3
• Bases also interact with alpha1-acid gp (0.4-1.0 g/L)

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 charge-
charge repulsion with phosphate head-group
+
R NH3
R O

Distribution - Vss
• What effect does plasma and tissue binding have on

the values of VSS that we observe?
fuP
VSS = 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)

Distribution - Vss VSS = Vp + ( VT.
fuP
fuT
)
• Acids tend to be highly plasma

Clinically-used
Clinically-usedDrugs
Drugs
protein bound; hence fuP is
100
small 100
Acid
Acid
10
10
• Acids have low tissue affinity
(L/kg)
Vss(L/kg)
11
due to charge repulsion; hence
Vss
fuT is large 0.1
0.1
0.01
• Acids therefore tend to have 0.01
-2-2 -1-1 00 11 22 33 44 55
low VSS (< 0.5 L/kg) LogD
LogD

fuP
fuT
)
• Neutrals have affinity for both

Clinically-used
Drugs
plasma protein and tissue
100
100 Neutral
• Affinity for both is governed Neutral
10
10
by lipophilicity
(L/kg)
Vss(L/kg)
11
• Changes in logD tend to
Vss
0.1
0.1
result in similar changes (in
0.01
0.01
direction at least) to both fuP -2-2 -1-1 00 11 22 33 44 55
and fuT LogD
LogD
• Neutrals tend to have

moderate VSS (0.5 – 5 L/kg)

fuP
fuT
)
• Bases have higher affinity for Clinically-used

Drugs
tissue due to charge
attraction 100
100
Base
Base
(L/kg)
• fuP tends to be (much) larger 10
Vss(L/kg)
10
than fuT 11
Vss
• Bases tend to have high VSS 0.1
0.1
(>3 L/kg) -2-2 -1-1 00 11 22 33 44 55
LogD
LogD

fuP
fuT
)
Clinically-used
Drugs
100
100 Acid
Acid
Base
Base
Neutral
Neutral
10
10
Vss (L/kg)
Vss (L/kg)
11
0.1
0.1
0.01
0.01
-2-2 -1-1 00 11 22 33 44 55
LogD
LogD

Distribution – effect of pH
• Distribution
– Ion trapping of basic compounds
• Distribution/Excretion
– Aspirin overdose & salicylate poisoning

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

Distribution: Ion trapping
• Ion trapping of a weak base pKa 8.5
Membrane
Plasma Cytosol
pH 7.4 pH 7.2
7.4 B B 4.8
92.6 BH+ BH+ 95.2
Distribution
Distribution
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).

• Ion trapping of a weak base pH 8.5

Membrane Membrane
Plasma Cytosol Lysosome
pH 7.4 pH 7.2 pH 4.8
B 4.8 B 0.02
7.4 B
92.6 BH+ BH+ 95.2 BH+ 99.8
Distribution
Distribution

OH O
• Effect of lysosomal uptake is HO O
O
more profound for dibasics HO O
HO N
OO O
• Theoretical lysosome:plasma
HO
ratio of ~ 160,000 O
Erythromycin VSS = 0.5 L/kg

• Apparent volume of liver may
be 1000 X physical volume
N
• Azithromycin achieves in vivo HO OH

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

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
• 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…………

1 pH 7.4 8000 Normal
OH OH
Bicarbonate
BRAIN OH O
BLOOD
O O
4 pH 6.8 8000 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.
KIDNEY
BLOOD URINE
Reabsorption 1 pH 6.0 300
Bicarbonate
OH OH OH OH
OH O Filtration OH O
O O O
O
Unbound fraction of both Reabsorption

species is filtered; Only 0.01 pH 8.0 300
neutral species is reabsorbed
• Bicarbonate incrseases urine pH leading to significantly

decreased reabsorption and hence increased excretion
Metabolism: lipophilicity
OH
X
N
N
Metabolic stability
OH
NH
OGluc
-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

Metabolism vs. Excretion
• Effect of logD on renal and metabolic clearance for a
series of chromone-2-carboxylic acids
16
Renal Replotted from Smith et al.,
14
Metabolic (1985) Drug Metabolism
Reviews, 16, p365
Clearance (ml/min/kg)
12
10
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
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

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

References & Further Reading
• MacIntyre and Cutler (1988). The potential role of lysosomes in the tissue
distribution of weak bases. Biopharmaceutics and Drug Disposition, 9, 513-
526
• 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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The Influence of Physicochemical

Iain Martin; Physchem Forum 2 1

A quick tour of the influence of physicochemical

Iain Martin; Physchem Forum 2 2

• Aqueous solubility is a prerequisite for absorption

• Therefore, a balance of physicochemical

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

Iain Martin; Physchem Forum 2 4

Strong relationship between permeability and logD

Iain Martin; Physchem Forum 2 6

• Issues of Solubility and membrane retention

Gut lumen Blood stream

(weak) ACIDS (weak) BASES

Iain Martin; Physchem Forum 2 9

Iain Martin; Physchem Forum 2 10

Polar Surface Area

Iain Martin; Physchem Forum 2 11

• Lipinski’s “Rule of 5”: Poor absorption is more

• Together, these parameters are descriptive of

Molecular weight and lipophilicity

Iain Martin; Physchem Forum 2 13

• The number of rotatable bonds (molecular flexibility) may

Iain Martin; Physchem Forum 2 15

• Oprea et al., (2001). Property distribution analysis of leads and drugs.

∆MW ∆HAC ∆RTB ∆HDO ∆cLogP ∆cLogD

Mean 89 1.0 2.0 0.2 1.16 0.97

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

Iain Martin; Physchem Forum 2 16

Iain Martin; Physchem Forum 2 17

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

Iain Martin; Physchem Forum 2 19

• What effect does plasma and tissue binding have on

Vp = physiological volume of plasma

Iain Martin; Physchem Forum 2 20

• Acids tend to be highly plasma

Iain Martin; Physchem Forum 2 21

• Neutrals have affinity for both

• Neutrals tend to have

Iain Martin; Physchem Forum 2 22

• Bases have higher affinity for Clinically-used

Iain Martin; Physchem Forum 2 23

Iain Martin; Physchem Forum 2 24

Iain Martin; Physchem Forum 2 25

Iain Martin; Physchem Forum 2 26

• Ion trapping of a weak base pKa 8.5

92.6 BH+ BH+ 95.2

• Lysosomes are membrane-enclosed organelles

Iain Martin; Physchem Forum 2 28

• Ion trapping of a weak base pH 8.5

92.6 BH+ BH+ 95.2 BH+ 99.8

Iain Martin; Physchem Forum 2 29

Erythromycin VSS = 0.5 L/kg

• Azithromycin achieves in vivo HO OH

Azithromycin VSS = 28 L/kg

Iain Martin; Physchem Forum 2 30

• Aspirin (acetylsalicylic acid) is metabolised to the active component

Iain Martin; Physchem Forum 2 32

4 pH 6.8 8000 Acidosis

• Acidosis leads to increase in unionised salicylate in the blood,

Reabsorption 1 pH 6.0 300

Unbound fraction of both Reabsorption

• Bicarbonate incrseases urine pH leading to significantly

As a general rule, liability to metabolism increases with increasing