iain martin; physchem forum 2 1 the influence of physicochemical properties on adme iain martin
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Iain Martin; Physchem Forum 2 1
The Influence of Physicochemical The Influence of Physicochemical Properties on ADMEProperties on ADME
Iain MartinIain Martin
Iain Martin; Physchem Forum 2 2
Physchem and ADMEPhyschem and ADME
A quick tour of the influence of physicochemical properties on:
Absorption
Distribution
Metabolism
Excretion
Iain Martin; Physchem Forum 2 3
• Aqueous solubility is a prerequisite for absorption
• Aqueous solubility and membrane permeability tend to work in “opposite directions”
• Therefore, a balance of physicochemical properties is required to give optimal absorption
Absorption: solubility & permeabilityAbsorption: solubility & permeability
aq. solubilityaq. solubility
permeabilitypermeability
Iain Martin; Physchem Forum 2 4
Absorption: solubility & permeabilityAbsorption: solubility & permeability
Lipinski (2000) J. Pharmacol. Toxicol. Meth., 44, p235
Iain Martin; Physchem Forum 2 5
Absorption: permeabilityAbsorption: 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
Iain Martin; Physchem Forum 2 6
Permeability: Caco2 assayPermeability: Caco2 assay
y = -0.2183x2 + 0.8639x + 0.4508R2 = 0.5362
-0.5
0
0.5
1
1.5
2
-1 0 1 2 3 4 5
clogD7.4
Lo
g P
ap
p
Strong relationship between permeability and logD
Riley et al., (2002) Current Drug Metabolism, 3, p527
Iain Martin; Physchem Forum 2 7
Permeability: Caco2 assayPermeability: Caco2 assay
NeutralBasic
Pap
p
LogP
• Issues of Solubility and membrane retention
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Absorption - ionisationAbsorption - ionisation
• The central principle is that only unionised (neutral) form of drugs will cross a membrane
Gut lumen Blood stream
HA H+ + A-
Blo
od
flow
H+ + A- HA
AbsorptionAbsorption
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Absorption - ionisationAbsorption - ionisation
• In man, stomach is ~ pH 2 and small intestine ~ pH 6
(weak) ACIDS
• Unionised form is more prevalent in the stomach.
• Although some absorption of acids takes place in the stomach, absorption also occurs in small intestine due to:
• Very large surface area (600x cylinder)
• Removal of cpd by PPB & blood flow
• Ionisation of cpd in blood shifts equilibrium in favour of absorption
(weak) BASES
• Unionised form is more prevalent in the small intestine.
• Bases are well absorbed from small intestine
• Very large surface area
• Removal of cpd by blood flow
• Ionisation equilibrium is countered by distributional factors
Iain Martin; Physchem Forum 2 10
Absorption – H-bondingAbsorption – 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
N N
NN
NH2
NH2 NH2N N
NN
N
N N
H
H H
H
H H
O
HH
OH
H
O
HH
O
HH
O H
H
O
H
H
N N
NN
N
N N
H
H H
H
H H
Iain Martin; Physchem Forum 2 11
Absorption: PSAAbsorption: 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
0
50
100
150
200
250
0
20
40
60
80
10
0
12
0
14
0
16
0
18
0
20
0
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0
24
0
26
0
Polar Surface Area
Fre
quen
cy
non-CNS
CNS
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 al., (1999) Pharmaceutical Research, 16, 1514
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Oral drug propertiesOral 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
Iain Martin; Physchem Forum 2 13
Oral drug propertiesOral drug properties
0
5
10
15
20
25
100 200 300 400 500 600 700 800 900
Mwt
coun
t % pdr99
0
5
10
15
20
25
100 200 300 400 500 600 700 800 900
Mwt
coun
t % pdr99
0
5
10
-5 -2.5 0 2.5 5 7.5 10
ACDlogPc
ou
nt
%
PDR99
0
5
10
-5 -2.5 0 2.5 5 7.5 10
ACDlogPc
ou
nt
%
PDR99
Molecular weight and lipophilicity
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Oral drug propertiesOral drug properties
05
10152025303540
0 4 8 12 16 20
Acceptors
coun
t % PDR99
05
10152025303540
0 4 8 12 16 20
Acceptors
coun
t % PDR99
0
5
10
15
20
25
30
35
0 2 4 6 8 10
Donorsc
ou
nt
%
PDR99
0
5
10
15
20
25
30
35
0 2 4 6 8 10
Donorsc
ou
nt
%
PDR99
• The number of rotatable bonds (molecular flexibility) may also be important…………..
Hydrogen bonding
Iain Martin; Physchem Forum 2 15
Oral drug propertiesOral 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
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
Iain Martin; Physchem Forum 2 16
• 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 and more lipophilic, we need to make sure that we start from Lead-Like properties rather than Drug-Like properties
Are Leads different from Drugs?Are Leads different from Drugs?
ΔMW ΔHAC ΔRTB ΔHDO ΔcLogP ΔcLogD
Mean 89 1.0 2.0 0.2 1.16 0.97
Iain Martin; Physchem Forum 2 17
Distribution: Plasma and Tissue binding 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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• 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
• Bases also interact with alpha1-acid gp (0.4-1.0 g/L)
Distribution: Plasma and Tissue binding Distribution: Plasma and Tissue binding
NH
NH
NH3
+
O
R1
O
R2
HA H+ + A-
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Plasma and Tissue binding (pH 7.4) Plasma and Tissue binding (pH 7.4)
• Tissue cell membranes contain negatively-charged phospholipid
R O
O
R NH3+
• Acids tend not to have any tissue affinity due to charge-charge repulsion with phosphate head-group
• Bases tend to have affinity for tissues due to charge-charge interaction with phosphate head-group
Iain Martin; Physchem Forum 2 20
Distribution - Vss Distribution - Vss
• What effect does plasma and tissue binding have on the values of VSS that we observe?
)fu
fu.V(VV
T
PTpSS )
fu
fu.V(VV
T
PTpSS
Vp = physiological volume of plasmaVT = physiological volume of tissue(s)fup = fraction unbound in plasmafuT = fraction unbound in tissue(s)
Iain Martin; Physchem Forum 2 21
• AcidsAcids tend to be highly plasma protein bound; hence fuP is small
• Acids have low tissue affinity due to charge repulsion; hence fuT is large
• Acids therefore tend to have low VSS (< 0.5 L/kg)
Distribution - Vss Distribution - Vss
Clinically-used Drugs
0.01
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogDV
ss (
L/k
g)
Acid
Clinically-used Drugs
0.01
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogDV
ss (
L/k
g)
Acid
)fu
fu.V(VV
T
PTpSS )
fu
fu.V(VV
T
PTpSS
Iain Martin; Physchem Forum 2 22
Distribution - Vss Distribution - Vss
Clinically-used Drugs
0.01
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogD
Vs
s (
L/k
g)
Neutral
Clinically-used Drugs
0.01
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogD
Vs
s (
L/k
g)
Neutral
• NeutralsNeutrals have affinity for both plasma protein and tissue
• Affinity for both is governed by lipophilicity
• 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)
)fu
fu.V(VV
T
PTpSS )
fu
fu.V(VV
T
PTpSS
Iain Martin; Physchem Forum 2 23
Distribution - Vss Distribution - Vss
• BasesBases have higher affinity for tissue due to charge attraction
• fuP tends to be (much) larger than fuT
• Bases tend to have high VSS (>3 L/kg)
Clinically-used Drugs
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogD
Vss
(L
/kg
)
Base
Clinically-used Drugs
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogD
Vss
(L
/kg
)
Base
)fu
fu.V(VV
T
PTpSS )
fu
fu.V(VV
T
PTpSS
Iain Martin; Physchem Forum 2 24
Distribution - Vss Distribution - Vss
Clinically-used Drugs
0.01
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogD
Vs
s (
L/k
g)
Acid
Base
Neutral
Clinically-used Drugs
0.01
0.1
1
10
100
-2 -1 0 1 2 3 4 5
LogD
Vs
s (
L/k
g)
Acid
Base
Neutral
)fu
fu.V(VV
T
PTpSS )
fu
fu.V(VV
T
PTpSS
Iain Martin; Physchem Forum 2 25
Distribution – effect of pHDistribution – effect of pH
• Distribution
– Ion trapping of basic compounds
• Distribution/Excretion
– Aspirin overdose & salicylate poisoning
Iain Martin; Physchem Forum 2 26
Distribution: Ion trappingDistribution: 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
Iain Martin; Physchem Forum 2 27
Distribution: Ion trappingDistribution: Ion trapping
• Ion trapping of a weak base pKa 8.5
MembranePlasma pH 7.4
Cytosol pH 7.2
BB
BH+
7.4
92.6 BH+
4.8
95.2
DistributionDistribution
Iain Martin; Physchem Forum 2 28
Ion trapping: lysosomesIon 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).
Iain Martin; Physchem Forum 2 29
• Ion trapping of a weak base pH 8.5
Ion trapping: lysosomesIon trapping: lysosomes
MembranePlasma pH 7.4
Cytosol pH 7.2
BB
BH+
7.4
92.6 BH+
4.8
95.2
MembraneLysosome pH 4.8
B
BH+
0.02
99.8
DistributionDistribution
Iain Martin; Physchem Forum 2 30
Ion trapping: lysosomesIon trapping: lysosomes
• Effect of lysosomal uptake is more profound for dibasics
• Theoretical lysosome:plasma ratio of ~ 160,000
• 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
O
OH
O
O
OH
O
O
O
NO
O
OH
OH
OH
O
OH
OO
OH
O
O
O
N
N
OOH
OHOH
Erythromycin VSS = 0.5 L/kg
Azithromycin VSS = 28 L/kg
Iain Martin; Physchem Forum 2 31
Salicylate poisoningSalicylate poisoning
• 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
O
O
OH
O
OH
O
OH
O
O
OH
O
OH
O
OH
Iain Martin; Physchem Forum 2 32
Salicylate poisoningSalicylate 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…………
Iain Martin; Physchem Forum 2 33
Salicylate poisoningSalicylate poisoning
BLOOD
OH
O
OH
OH
O
O
1 pH 7.4 8000
4 pH 6.8 8000
BRAIN
• 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.
Normal
Acidosis
Bicarbo
nate
Iain Martin; Physchem Forum 2 34
OH
O
OH
OH
O
O
Salicylate poisoningSalicylate poisoning
BLOOD
OH
O
OH
OH
O
O
KIDNEY
1 pH 6.0 300
0.01 pH 8.0 300
Filtration
Reabsorption
• Bicarbonate incrseases urine pH leading to significantly decreased reabsorption and hence increased excretion
URINE
Reabsorption
Bicarbo
nate
Unbound fraction of both species is filtered; Only neutral species is reabsorbed
Iain Martin; Physchem Forum 2 35
Metabolism: lipophilicityMetabolism: lipophilicity
N
OH
N
OGluc
NH
OH
-1 0 1 2 3 4
logD
Me
tab
oli
c s
tab
ilit
y
N
X
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
Iain Martin; Physchem Forum 2 36
Metabolism vs. ExcretionMetabolism vs. Excretion
0
2
4
6
8
10
12
14
16
-1 -0.5 0 0.5 1 1.5 2
LogD
Cle
aran
ce (
ml/m
in/k
g)
Renal
Metabolic
• Effect of logD on renal and metabolic clearance for a series of chromone-2-carboxylic acids
Replotted from Smith et al., (1985) Drug Metabolism Reviews, 16, p365
• Balance between renal elimination into an aqueous environment and reabsorption through a lipophilic membrane
Iain Martin; Physchem Forum 2 37
Renal ExcretionRenal Excretion
• Effect of LogD on renal clearance of -blockers
• Note that only unbound drug is filtered and that PPB increases with logD
Van de Waterbeemd et al., (2001) J. Med. Chem, 44, p1313
Iain Martin; Physchem Forum 2 38
SummarySummary
• 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
Iain Martin; Physchem Forum 2 39
References & Further ReadingReferences & 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