Ian Martin Slides PDF - PhysChem Forum

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The Influence of Physicochemical The Influence of Physicochemical Properties on ADMEProperties on ADME

Iain MartinIain Martin


Physchem and ADMEPhyschem and ADME

A quick tour of the influence of physicochemicalproperties on:

Absorption

Distribution

Metabolism

Excretion


• 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


Absorption: solubility & permeabilityAbsorption: solubility & permeability

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


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


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

Log

P app

Strong relationship between permeability and logD

Riley et al., (2002) Current Drug Metabolism, 3, p527


Permeability: Caco2 assayPermeability: Caco2 assay

NeutralBasic

P app

LogP

• Issues of Solubility and membrane retention


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-

Blood flow

H+ + A- HA

AbsorptionAbsorption


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


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

OH H

O

HH O H

H

O

HH

N N

NN

N

N N

H

H H

H

H H


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 80 100

120

140

160

180

200

220

240

260

Polar Surface Area

Freq

uenc

y

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


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



0

5

10

15

20

25

100 200 300 400 500 600 700 800 900

Mwt

cou

nt

%

pdr99

0

5

10

15

20

25

100 200 300 400 500 600 700 800 900

Mwt

cou

nt

%

pdr99

0

5

10

-5 -2.5 0 2.5 5 7.5 10

ACDlogP

coun

t %

PDR99

0

5

10

-5 -2.5 0 2.5 5 7.5 10

ACDlogP

coun

t %

PDR99

Molecular weight and lipophilicity



05

10152025303540

0 4 8 12 16 20

Acceptors

cou

nt

%

PDR99

05

10152025303540

0 4 8 12 16 20

Acceptors

cou

nt

%

PDR99

0

5

10

15

20

25

30

35

0 2 4 6 8 10

Donors

coun

t %

PDR99

0

5

10

15

20

25

30

35

0 2 4 6 8 10

Donors

coun

t %

PDR99

• The number of rotatable bonds (molecular flexibility) may also be important…………..

Hydrogen bonding


Oral drug propertiesOral drug properties95th (5th) percentile

5.7 (0.4) 6.2 (-1.2)cLogP914Rot. Bond35HBD59HBA

73127PSA449611Mol. Wt.

CNSNon-CNS

• In general, CNS drugs are smaller, have less rotatable bonds andoccupy a narrower range of lipophilicities. They are also characterised by lower H-bonding capacity


• 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?

∆MW ∆HAC ∆RTB ∆HDO ∆cLogP ∆cLogD

Mean 89 1.0 2.0 0.2 1.16 0.97


Distribution: Plasma and Tissue bindingDistribution: 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


• 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 highlybound due to charge-charge interaction with lysine

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

Distribution: Plasma and Tissue bindingDistribution: Plasma and Tissue binding

NH

NH

NH3+

O

R1

O

R2

HA H+ + A-


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


Distribution - VssDistribution - Vss

• What effect does plasma and tissue binding have on the values of VSS that we observe?

)fufu.V(VV

T

PTpSS +=

Vp = physiological volume of plasmaVT = physiological volume of tissue(s)fup = fraction unbound in plasmafuT = fraction unbound in tissue(s)


•• 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)


Clinically-used Drugs

0.01

0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

Acid


0.01

0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

Acid

)fufu.V(VV

T

PTpSS +=




0.01

0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

Neutral


0.01

0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(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)

)fufu.V(VV

T

PTpSS +=



•• 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)


0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

Base


0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

Base

)fufu.V(VV

T

PTpSS +=




0.01

0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

AcidBaseNeutral


0.01

0.1

1

10

100

-2 -1 0 1 2 3 4 5

LogD

Vss

(L/k

g)

AcidBaseNeutral

)fufu.V(VV

T

PTpSS +=


Distribution – effect of pHDistribution – effect of pH

• Distribution– Ion trapping of basic compounds

• Distribution/Excretion– Aspirin overdose & salicylate poisoning


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


Distribution: Ion trappingDistribution: Ion trapping

• Ion trapping of a weak base pKa 8.5

MembranePlasmapH 7.4

CytosolpH 7.2

BB

BH+

7.4

92.6 BH+

4.8

95.2

DistributionDistribution


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).


• Ion trapping of a weak base pH 8.5


MembranePlasmapH 7.4

CytosolpH 7.2

BB

BH+

7.4

92.6 BH+

4.8

95.2

Membrane LysosomepH 4.8

B

BH+

0.02

99.8

DistributionDistribution



• 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 vivotissue: plasma ratios of up to 100-fold and is found predominantly in lysosome-rich tissues

OOH

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


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



• 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…………



BLOODOH

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

Bicarbonate


OH

O

OH

OH

O

O


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

Bicarbonate

Unbound fraction of both species is filtered; Only neutral species is reabsorbed


Metabolism: lipophilicityMetabolism: lipophilicity

N

OH

N

OGluc

NH

OH

-1 0 1 2 3 4

logD

Met

abol

ic s

tabi

lity

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


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 (m

l/min

/kg)

RenalMetabolic

• 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


Renal ExcretionRenal Excretion

• Effect of LogD on renal clearance of β-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


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


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

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