Lipophilicity, Partitioning and Distribution of Drug

Question 1

Introduction

Measured permeability of drugs is often viewed as a surrogate property to predict ORAL drug absorption

This approach approximates transport of drugs taking into consideration ONLY passive transcellular drug diffusion through the bilayer lipid membrane

Question 2

Partitioning of drugs

In the body there are a number of important barriers which a drug has to cross before it becomes effective

What are these important barriers?

Answer 2

These include: the Gastrointestinal Tract (GIT) and the Blood-Brain Barriers (BBB):

GIT (aq) ———————–> Blood stream (aq)
.lipid (cell membranes)

Bloodstream (aq) ——————> CNS/Brain(aq)
.lipid (cell membranes)

(arrow represents it crossing lipid membrane)

Question 3

Model of a biological membrane
(Diagram in notes)

Question 4

Membrane barrier penetration

What are the barriers that drugs (organic compounds) have to cross to reach their biological targets?

Answer 4

Cellular membranes are the barriers that drugs (organic compounds) have to cross to reach their biological targets

Question 5

Are membranes hydrophilic or hydrophobic and why?

Answer 5

Biological membranes are hydrophobic in nature (or non-polar) as they are composed of phospholipids containing long hydrocarbon chains

Question 6

To pass the cellular membranes and reach their biological targets what solutions do the drugs need to pass from and to?

Answer 6

To succeed in its mission, the drug must pass from the aqueous solution of the extracellular fluid to the aqueous solution of the intracellular fluid by crossing the lipid membrane

Question 7

What characteristic must drugs have to pass across the lipid membrane between these two solutions?

Answer 7

The drug must be sufficiently soluble in both aqueous and the lipid phases to effectively travel to its site of action

Question 8

Model to Approximate Biological barriers

(Information flashcard- no need to memorise)

Answer 8

The properties of some organic solvents (e.g. n-octanol, cyclohexane, etc) are thought to resemble those of lipid bilayer membranes

It has therefore been suggested that distribution of drugs into hydrophobic organic media (e.g. n-octanol or cyclohexane) simulates, to a certain extent, their ability to passively diffuse across biological membranes

We can therefore approximate biological barriers (i.e. cellular membranes) with the system consisting of two immiscible liquids (liquids that do not mix), one aqueous and another organic.

The movement (or redistribution) of organic compounds from one liquid to another is called PARTITIONING

Question 9

What is partitioning?

Answer 9

The movement (or redistribution) of organic compounds from one liquid to another.

Question 10

What happens if you add an excess of an organic compound to a mixture of two immiscible liquids?

Answer 10

If an excess of an organic compound is added to a mixture of two immiscible liquids, it will partition itself between the two liquids so that each becomes SATURATED

Question 11

What will happen if the amount of compound added is not sufficient to saturate the solutions?

Answer 11

If however the amount of compound added is not sufficient to saturate the solutions, it will be distributed between the two immiscible liquids according to a definite concentration ratio:
C org (organic phase) ⇌ C aq (aqueous phase)

Question 12

What is a Saturated solution? (one definition required)

Answer 12

A saturated solution contains the maximum amount of solute that can dissolve in a solvent at a given temperature and pressure. However, a saturated solution may not be concentrated if the maximum solubility is low.

A liquid is said to be saturated when it contains so much of a solute at that temperature that it can dissolve no more.

a diluted solution is when the amount of solute in the solvent is very low. a concentrated solution has just the right amount of solute, while. a saturated solution has too much.

Question 13

What is Partition Coefficient(P)?

• Give the equation

Answer 13

Partition Coefficient (P) is a constant.
It is defined as the ratio of concentration of compound in organic phase to the concentration in aqueous phase at EQUILIBRIUM

Definition/equation:

P = C org/C aq

Where:
C org – concentration of the drug in organic layer
C aq – concentration of the drug in aqueous layer

Question 14

What is the Partition Coefficient of unionised drug called?

Answer 14

The Partition Coefficient of UNIONISED drug is called TRUE Partition Coefficient (PTRUE)

Question 15

Explain what it means if PTRUE is greater than 1 or less than 1

Answer 15

If PTRUE is greater than 1 then Corg > Caq and the compound is HYDROPHOBIC (or LIPOPHILIC)
- (Concentration of drug in the organic layer is greater than the concentration of drug in the aqueous layer)

If PTRUE less than 1 then Corg < Caq and the compound is HYDROPHILIC (LIPOPHOBIC or POLAR)
- (Concentration of drug in the organic layer is less than the concentration of drug in the aqueous layer)

Question 16

How do you calculate Log P?

Answer 16

Log P= Log 10 (Partition Coefficient)

Question 17

What does it mean if Log P = 1, 0 or -1

(what does P equal and what is the C org: C aq ratio)

Answer 17

Log P = 1 means that P (Partition Coefficient) = 10 and Corg : Caq = 10 : 1
(i.e. solubility of the compound in organic phase is 10 times higher than in aqueous phase)

Log P = 0 means that P = 1 and Corg : Caq = 1 : 1
(i.e. the compound has an equal solubility in organic and aqueous phases)

Log P = -1 means that P = 0.1 and Corg : Caq = 1 : 10
(i.e. solubility of the compound in organic phase is 10 times lower than in aqueous phase)

Question 18

Partition coefficients of common drugs

Answer 18

Drug P Log P

Naproxen 1050 3.02
Medazepam 794 2.9
Diazepam 7.94 0.9
Warfarin 1.58 0.2
Oxazepam 0.79 -0.1
Hydrocortisone Acetate 0.05 -1.3

(Drugs at the top are more hydrophobic, drugs at the bottom are more polar)
(Diagram in notes)

Question 19

How do you get from Log P to P?

Answer 19

P= 10^logP

Question 20

What is partition coefficient used to predict?

Answer 20

Partition Coefficient can be used to predict the absorption, distribution and elimination of drugs within the body

Question 21

What is chemical polarity?

Answer 21

Describes how equally bonding electrons are shared between atoms

It is a physical property of compounds and affects other physical properties, e.g. solubility

Question 22

What does chemical polarity affect?

Answer 22

Polarity affects other physical properties (e.g. solubility) and also affects intermolecular forces, leading to some compounds or molecules within compounds being recognized as polar or non-polar

Question 23

Polarity of Molecules

(this can just be an information flashcard as I already know this from A Level, can be asked to recite this after reading)

Answer 23

Electrons are not always shared equally between two bonding atoms

Atoms with high electronegativities (e.g. fluorine, oxygen, and nitrogen) exert a greater pull of electrons than atoms with lower electronegativities

In a bonding situation this can lead to unequal sharing of electrons between atoms as electrons will spend more time closer to the atom with the higher electronegativity

The unequal sharing of electrons within a bond leads to the formation of an electric dipole: a separation of positive and negative electric charge

Question 24

What does polarity refer to?

What is Molecular polarity dependent on?

Answer 24

Polarity refers to the dipole-dipole intermolecular forces between the slightly positively-charged end of one molecule to the negative end of another molecule

Molecular polarity is dependent on the difference in electronegativity between atoms in a compound and the asymmetry of the chemical structure

Question 25

Why is water thought of to be polar?

What are compounds that have the capacity to form hydrogen bonds with water considered to be?

Why is Methane considered to be non-polar?

Answer 25

Water is thought of to be polar because of the uneven sharing of its electrons

Compounds that have the capacity to form hydrogen bonds with water are considered to be hydrophilic or polar

However, methane is considered non-polar because the carbon shares the hydrogen molecules uniformly

Question 26

What do the Hansch-Fujita parameters describe or tell you?

Answer 26

The Hansch-Fujita parameters (π) describe the contribution of various functional groups to the lipophilicity of a compound

Question 27

What do hydrophobic functional groups include?

What value is their Hansch-Fujita hydrophobic parameters?

What does a predominance of these groups lead to and what affect does it have on the molecule?

Answer 27

Hydrophobic functional groups include:
- Aromatic Hydrocarbons
- Aliphatic Hydrocarbons
- Halogens

Their Hansch-Fujita Hydrophobic parameter is (+π)
(They have positive Hansch-Fujita parameters)

A predominance of (+π) groups will lead to an increase in Partition Coefficient

This will make the molecule more lipid soluble and better able to pass through the lipid membranes

Question 28

Hansch-Fujita parameters (+π) for hydrophobic organic fragments

Answer 28

FRAGMENT______________________ π value
-CH- ; -CH2- and CH3 (aliphatic) ___+0.56
-CH2-CH3 _________________________+1.12
Phenyl_____________________________+2.0
-F__________________________________+0.14
-Cl_________________________________+0.71
-Br_________________________________+0.86
-I__________________________________+1.12
-CF3_______________________________+0.88
IMHB-Intramolecular Hydrogen Bond +0.65
-SH________________________________+0.39
S____________________________________0.0

(Diagram in notes)

Question 29

What do hydrophilic functional groups include?

What value is their Hansch-Fujita hydrophilic parameters?

What does a predominance of these groups lead to and what affect does it have on the molecule?

Answer 29

Hansch-Fujita Hydrophilic parameter is (-π)
(They have negative Hansch-Fujita parameters)

(should be called Hansch-Fujita Hydrophobic parameter not hydrophilic I think??)

A predominance of (-π) groups will lead to a decrease in Partition Coefficient

This will make the molecule less lipid soluble and less able to pass through the lipid membranes

Question 30

Hansch-Fujita parameters (-π) for hydrophilic organic fragments

Answer 30

FRAGMENT_________________________π value
S____________________________________0.0
-NO2 (aromatic)_____________________-0.28
O=C-O- (ester)_______________________-0.64
-COOH (carboxylic acid)_____________-0.7
-COO- (carboxylate)_________________-4.34
-OH (hydroxyl, phenol)______________-0.67
-NH2 (amine)________________________-1.23
-NH3+ (ammonium)_________________-4.19
C=O (aldehyde, ketone)_____________-0.65
-COCH3 (acetyl)_____________________-0.55
-CONH2, -CONH-(formamide, amide)-1.49
-SO2(NH2) (sulfonamide)____________-1.82
R1-O-R2 (ether)______________________-0.78

(Diagram in notes)

Question 31

Some examples of drug properties
(Diagram in notes)

Question 32

Some examples of drug properties

Answer 32

Captopril:
PTrue = 2.2 (Exp)
Log P = 0.34 (Exp)
pKa ~3.7

Ibuprofen:
PTrue = 9332 (Exp)
Log P = 3.97 (Exp)
pKa ~ 4.6

Question 33

Why would ibuprofen have a much higher True Partition coefficient than captopril and be better absorbed orally? - (see structures for assistance)

Answer 33

Ibuprofen should have a much higher True Partition Coefficient than Captopril (see actual values) and should be much better absorbed orally (particularly from the stomach where the -COOH group will be UNIONISED). This is because ibuprofen has more hydrophobic/ lipophilic groups (compared to hydrophilic groups)

Question 34

SUMMARY

The Partition Coefficient is a very useful parameter

May be used in combination with the pKa to predict the distribution of a drug compound in a biological system

Factors such as absorption, excretion and penetration of the CNS may be related to the Log P value of a drug, and in certain cases predictions can be made

Question 35

Effect of pH and drug ionisation

If the drug is a weak acid or a weak base what will considerably alter the partitioning of the compound?

How much higher is the permeability of the unionised form of a drug across a phospholipid membrane by passive diffusion than the ionised form?
(Or how much higher is the permeability of the unionised form than the ionised form?)

Answer 35

If the drug is a weak acid or a weak base then ionisation will considerably alter the partitioning of the compound

It has been estimated that the permeability of the unionised form of a drug across a phospholipid membrane by passive diffusion is about 108 higher than that of the ionised form

Question 36

(just an information flashcard)

Therefore, in our approach we assume that only the UNIONISED drug will partition into the hydrophobic organic layer
(Ionised form cannot pass from aqueous phase to the organic phase but the unionised, neutral form can)

According to this approximation, the drug needs to be in its uncharged (i.e. UNIONISED) form at the membrane surface to permeate the membrane by PASSIVE DIFFUSION

Question 37

What is the concentration of the compound passing through the membrane barrier dependent on?

What is this factor controlled by?

Answer 37

The concentration of the compound passing through the membrane barrier depends upon the % of compound which is UNONISED

The % of UNONISED compound is controlled by its pKa and pH of the solution

Question 38

Ionisation and Partition coefficient

For neutral compounds, weak acids and weak bases does the partition coefficient vary with changes in pH?

Answer 38

For a NEUTRAL compound (e.g. Chlorobenzene) Partition Coefficient is the same at ANY pH value
(as there are no changes in ionisation)

For weak acids and/or bases Partition Coefficient varies depending upon the pH at which it is measured (APPARENT Partition Coefficient, PAPPARENT )

NOTE: Sometimes PAPPARENT is called D or “Distribution Coefficient”

Question 39

What is the APPARENT Partition Coefficient dependent on?

What is the equation for the PAPPARENT?

Answer 39

The APPARENT Partition Coefficient (P APPARENT ) is dependent on the proportion UNIONISED form of the drug present in solution

PAPPARENT = PTRUE × f unionised

where f unionised is the fraction of the total amount of drug unionised at certain pH (fraction of unionised drug)

Question 40

What if the drug is totally unionised?

What is the fraction of the drug unionised dependent on?

Answer 40

If drug is totally UNIONISED, f unionised = 1 and thus PAPPARENT becomes equal to PTRUE

PAPPARENT = PTRUE x 1 –> PAPPARENT = PTRUE

The f unionised / fraction of the drug unionised is dependent upon the pH of the aqueous solution and the pKa of the drug

Question 41

Practical application for drugs with acidic functional groups

Can aspirin be absorbed in the stomach?
(can search up the structure which may help with visualisation or Diagram in notes)

Aspirin (pKa ~ 3.5)
Stomach pH ~ 2.0
(aspirin has a carboxylic acid functional group- responsible for pKa?)

Answer 41

Can use the Henderson-Hasselbalch equation to find out % of Aspirin which is ionised in the stomach (or use a stepwise approach using the Ka expression)

%ionised Aspirin in stomach =
100 / 1 + Antilog (pKa - pH)

(‘pKa - pH’ is ‘3.5 - 2’)

% ionised Aspirin in stomach= 3.07%
100 - 3.07 = 96.93
% Unionised Aspirin in stomach = 96.93

Aspirin is highly unionised in the stomach and thus can be absorbed

Question 42

Can use this method to figure out % ionised in blood
Blood stream pH~ 7.4
% ionised Aspirin in blood= 99.99%
In the bloodstream aspirin is highly ionised

Question 43

PTRUE and PAPPARENT of Aspirin

For Aspirin
P TRUE = 15.49
What is the P APPARENT at pH 2?

Answer 43

P APPARENT (pH 2):

P APPARENT (pH 2) = PTRUE × f unionised

% Unionised (pH 2) = 96.93% → f unionised = 0.9693

PAPPARENT (pH 2) = 15.49 × 0.9693 = 15.02

Question 44

Can use this method to figure out PAPPARENT at pH 7.4
PAPPARENT (pH 7.4) = 15.49 × 0.0001 = 0.0016

Question 45

Summary of Aspirin:
PTRUE = 15.49 Log P = 1.19 (Experimental data. Ref: Hansch C. et al. 1995)
PAPPARENT (pH 2) = 15.02
PAPPARENT (pH 7.4) = 0.0016

Question 46

Practical application for drugs with basic functional groups

Can the drug Diphenhydramine be absorbed in the stomach?

(Conjugate acid pKa 9.2)
Stomach pH ~ 2

Answer 46

% Ionised drug in stomach= 100 / 1 + Antilog (pH - pKa)

% Ionised drug in stomach= 100 / 1 + Antilog (-7.2)

% Ionised Drug in stomach = 99.9999937 %

In the stomach the drug is highly IONISED and thus NOT absorbed

Question 47

Can the drug Diphenhydramine be absorbed in the small intestine? pH~ 8.0
(pKa 9.2)

(Can look at notes for diagram)

Answer 47

Can use this method to figure out % ionised in the small intestine and so figure out whether it can be absorbed in the small intestine
Small intestine pH~ 8.0
% ionised Drug in small intestine= 94.07%
In the small intestine 5.93% of the drug is UNIONISED and thus can be absorbed

Question 48

PTRUE and PAPPARENT of Diphenhydramine

For Diphenhydramine
PTRUE = 1862 (Hansch C. et al. 1995)
What is the PAPPARENT at pH 2?

Answer 48

PAPPARENT (pH 2):
PAPPARENT (pH 2) = PTRUE × f unionised
% Ionised (pH 2) = 99.9999937 %
% Unionised (pH 2) = 0.63×10^(-5) %
funionised = 0.63 ×10^(-7)

PAPPARENT (pH 2) = 1862 × 0.63 ×10^(-7) = 0.00012

Question 49

Can use this method to figure out PAPPARENT at pH 8
PAPPARENT (pH 7.4) = 1862 × 0.0593 = 110.42

Question 50

Summary of Diphenhydramine :
PTRUE = 1862 Log P = 3.27
(Experimental data. Ref: Hansch C. et al. 1995)
PAPPARENT (pH 2) = 0.00012
PAPPARENT (pH 8) = 110.42

Question 51

Important distinction if drug is only absorbed in small intestine- there will be a delay in onset of action as drug has to pass through stomach first.

Therefore, patients taking antihistamine drugs for travel sickness need to take the drug at least one hour before travelling.