W5.1_Lipophilicity

Question 1

What is the purpose of measured permeability of drugs? What does it evaluate and in what environments are used?

Answer 1

• Surrogate property to predict oral drug absorption
• Only taking passive transcellular drug diffusion through bilayer membrane into consideration
• ≈ Evaluate drug’s ability to penetrate various biological barriers (ex. GI tract and blood-brain (BB) barriers), only through passive transcellular diffusion mechanisms by partitioning through cellular membrane
• GI tract(aq) -lipid cell membrane-> blood stream(aq) - Blood stream(aq) -lipid cell membrane-> CNS/brain(aq)

Question 2

Explain the importance of drug molecules being able to dissolve in both aqueous and organic phases. How can some organic solvents relate to this?

Answer 2

• ∵ Cellular membranes are hydrophobic in nature (phospholipids with long hydrocarbon tails)
• ∴ Drugs have to cross barriers to reach their biological targets
• Drug must be sufficiently soluble in both aq/org phases to pass from aqueous solution in extracellular fluid to the aqueous solution in intracellular fluid by crossing the lipid membrane
• ∵ Properties of some organic solvents (ex. n-octanol, cyclohexane) resemble lipid bilayer membranes
• ∴ They mimic biological barriers with system of two immiscible liquids (aq + org) to stimulate ability to passively diffuse across biological membranes

Question 3

What is partitioning? Describe the difference between saturation and unsaturation in partitioning. What is the partition coefficient and what is its purpose?

Answer 3

• Partitioning: movement/redistribution of organic compounds from one liquid to another
• If excess organic compound is added, partition itself between two liquids -> each becomes saturated
• Not in excess: distributed between two liquids in a definite concentration ratio (C(org) ⇌ C(aq))
• Partition coefficient P=C(org)/C(aq)(at eqm) -> predict absorption/distribution/elimination of drugs in body

Question 4

Explain P(TRUE) and LogP values, and also their indications.

Answer 4

• P(TRUE) (True partition coefficient) = P of unionised drug
• P(TRUE) > 1: C(org) > C(aq) -> compound is hydrophobic/lipophilic
• P(TRUE) < 1: C(org) < C(aq) -> compound is hydrophilic/lipophobic
• LogP > 0: higher solubility in organic phase
• LogP = 0: equal solubility
• Log P < 0: higher solubility in aqueous phase

Question 5

Explain the difference between chemical and molecular polarities.

Answer 5

• Chemical polarity: how equally bonding electrons are shared between atoms -> affect physical properties/ intermolecular forces
• Atoms with high electronegativity (FON) exert a greater pull of electrons -> electrons spend more time closer to the atom with higher electronegativity -> unequal sharing of electrons -> form an electric dipole
• Molecular polarity: dipole-dipole intermolecular forces between slightly positive charged end of one molecule and the slightly negative charged end of another molecule
• *Dependent on difference in electronegativity between atoms and asymmetry of chemical structure

Question 6

What are Hansch-Fujita paramters? What are the hydrophobic and hydrophlic parameters and how do they impact the lipophilicity of a molecule?

Answer 6

• Hansch-Fujita parameters (π): describe the contribution of various functional group to lipophilicity of compounds
• Hydrophobic parameters: aromatic/aliphatic hydrocarbons, halogens, intramolecular hydrogen bonds, -SH
• +π: increase P value -> higher lipid solubility, more able to pass through lipid membranes
• Hydrophilic parameters: hydroxyl groups, carboxyl groups, amines, ether, amides, -NO2, carbonyl groups, -SO2(NH2)
• -π: decrease P value -> lower lipid solubility, less able to pass through lipid membranes

Question 7

What is the general principle of permeability in acidic or basic drugs? Explain P(APPARENT) value and its application in drug absorption.

Answer 7

• Acidic/Basic drugs: ionised form is extremely much less permeable than unionised form
• ∴ Assume only unionised drug will partition into the hydrophobic organic layer
• Apparent partition coefficient OR Distribution coefficient
• P(APPARENT) OR D = P(TRUE) x f(unionised) (% unionised at certain pH)
• If drug is totally unionised: P(TRUE) = D
• Application ex.: if drug is only absorbed in small intestine -> delay in onset of action -> usually take the drug an hour early