Distribution Phenomena

Question 1

What must an oral drug do other than binding the target

Answer 1

 dissolve
 survive a range of pHs (1.5 to
8.0)
 survive intestinal bacteria
 cross membranes
 survive liver metabolism
 avoid active transport to bile
 avoid excretion by kidneys
 partition into target organ
 avoid partition into undesired
places (e.g. brain, foetus)

Question 2

What is ionisation?

Answer 2

protonation or deprotonation resulting in charged
molecules
 About 85% of marketed drugs contain functional groups that are
ionised to some extent at physiological pH (pH 1.5 – 8).

Question 3

What does the ionisation control

Answer 3

 Absorption and transport to site of action
• Solubility, bioavailability, absorption and cell penetration, plasma
binding, volume of distribution

 Binding of a compound at its site of action
• un-ionised form involved in hydrogen bonding
• ionised form influences strength of salt bridges or H-bonds

 Elimination of compound
• Biliary and renal excretion
• CYP P450 metabolism

Question 4

What is the acidity constant Ka

Ph= pka =50% ionised

Answer 4

pKa = -log10 Ka

Ka=H*A-/AH. %ionised= 100/1+10^pka-ph

Question 5

What are amphoteric drugs

Answer 5

can function as
either weak acids or weak bases in aqueous solution

Like H2PO4- and m-aminophenol

Question 6

What is lipophilicity

Answer 6

Lipophilicity (‘fat-liking’) is the most important physical property of a drug
in relation to its absorption, distribution, potency, and elimination

Question 7

What does lipophilicity affect

Answer 7

 Solubility
 Absorption
 Plasma protein binding
 Metabolic clearance
 Volume of distribution
 Enzyme / receptor binding
 Biliary and renal clearance
 CNS penetration
 Storage in tissues
 Bioavailability
 Toxicity

Question 8

 Placing a non-polar surface into water disturbs network of water-water
hydrogen bonds. This causes a reorientation of the network of hydrogen
bonds to give fewer, but stronger, water-water H-bonds close to the non-
polar surface.
 Water molecules close to a non-polar surface consequently exhibit
much greater orientational ordering and hence lower entropy than bulk
water.

Question 9

What happens if the compound is too lipophilic

Answer 9

 be insoluble in aqueous media (e.g. gastrointestinal fluid or blood)
 bind too strongly to plasma proteins and therefore the free blood
concentration will be too low to produce the desired effect
 distribute into lipid bilayers and be unable to reach the inside of the cell

Question 10

What happens if the compound is too polar

Answer 10

the compound is too polar, it may not be absorbed through
the gut wall due to lack of membrane solubility.

Question 11

What is the partitioning system

Answer 11

the drug will
partition (distribute) between the
two phases till it reach
equilibrium.
At equilibrium : G = 0

Question 12

What’s the equilibrium constant

Answer 12

The equilibrium constant , K, is known as the distribution
coefficient or partition coefficient.

K=C1/c2

Question 13

If a compound can ionise then the observed partitioning between water and
octanol will be pH dependent.

Answer 13

K= Ha octanol/ha aqueous* A- aqueous

Question 14

Partition coefficient P (usually expressed as log10P or logP) is defined as:

P =
[X]octanol
/[X]aqueous

Question 15

What is P

Answer 15

is a measure of the relative affinity of a molecule for the lipid and aqueous
phases in the absence of ionisation.

– log P > 1: lipophilic drug
– log P < 1: hydrophilic drug

Question 16

Remember: for ionizable drugs (weak
acidic and basic drugs) log P will be pH-
dependent. At different pH, the drug will
have different ratio of ionized to unionized
drug and therefore, different distribution
between water and octanol. (see
example next page)

Question 17

Remember
Acidic drug—- pH lower, bigger logP , more lipophilic
Basic drug —- pH higher, bigger logP , more lipophilic
Amphoteric drugs—— increase with pH increase until reaching the optimal pH then decreasing with increasing ph

Question 18

What is optimal P

Answer 18

It
depends on the route of administration of
the drug  it is different for different
membranes that the drug has to cross.
• As a general rule: maximum flux of drug
will occur at log P value = 3.

Question 19

What does logP affect

Answer 19

Binding to
enzyme /
receptor increases

Aqueous solubility Decreases with increasing logP

Binding to
P450
metabolising
enzymes increases

Absorption
through
membrane increasing

Binding to
blood / tissue
proteinsless drug free to act increasing

Binding to
hERG heart
ion channel -
cardiotoxicity
risk increasing