In general, the higher the lipophilicity of
a drug, the higher its membrane permeability
and therefore, the higher its metabolic clearance,
which is through the first-pass effect. Therefore,
it is important to balance lipophilicity with
So, modification of the drug structure can
alter the lipophilicity of the compound. Molecules
can be made more lipophilic by masking a polar
group such as an amine or an alcohol or a
carboxylic acid with an alkyl or acyl group.
This, however, may lead to reduction in activity,
if that polar group is actually required for
interaction with that receptor.
In this scenario, a temporary masking group,
prodrug, which we’ll discuss a little bit
later on, is something that has to be considered.
An example of such a prodrug approach would
be the conversion of a phenol or an alcohol
into an ester. The ester can then be hydrolysed
by esterases within the body, thus releasing
the active component from the prodrug.
Let’s have a quick look here at these two
examples. Tetracycline is an antibiotic. It’s
an antibiotic that interferes with protein
biosynthesis within prokaryotes or bacterial
cells. It is not particularly well absorbed.
However, by substituting a chlorine group
onto one of the… onto the only benzene ring
in the structure, you can improve the lipophilicity
and therefore, the absorption and oral bioavailability
Sometimes, the reverse is true. The metabolism
of something which is very lipophilic is actually
very… causes there to be less bioavailability.
It seems there would be less available to
actually work in the area where it’s supposed
to. And so, in this scenario, polar groups
can be added in order to render it less prone
to metabolism via the first pass.
An example here would be clotrimazole and
fluconazole. Note the lipophilicity of the
first, Canestan, and the fact that by adding
a polar group, in this case an OH group here.
In the case of fluconazole, we are actually
reducing the lipophilicity, making it more
Let’s have a quick look at another one,
an anti-viral, aprenavir: poor aqueous solubility
and therefore, a large number of excipients
are required resulting in a dose of around
8 capsules twice daily. This is obviously
a considerable burden in terms of patient
compliance. However, if we incorporate a phosphate
group into the molecule, giving us the prodrug
fosamprenavir, this dramatically increases
the aqueous solubility, resulting in a higher
drug load in the tablet and therefore, greater
bioavailability of the anti-viral itself.
The phosphate group removed by… is removed
by phosphatases yielding the parent drug and
here, we have the structures. They may appear
complex, but if we look to the right and see
aprenavir, we can see that there is a secondary
alcohol there joining the two aromatic systems.
If we convert that into a phosphate group,
such as in the case of fosamprenavir, we find
that those 2 OH groups attached to the phosphorus
are actually ionised at physiological pH and
exist as O- in both cases.
Of course, going back to where we were talking
about ion-dipole interactions, this means
that it’s possible for the negatively charged
O- on the fosamprenavir to interact strongly
with water molecules. This increases, of course,
the solubility because it is polar. By obviously
increasing the solubility, this increases
the bioavailability of the drug when taken
and reduces the number of tablets that need
to be given to a patient.
Most drugs are either weak acids or weak bases
containing, as they do, they are either carboxylic
acids or, for example, amines. And so, therefore,
they exist in equilibrium as both unionised
and ionised forms.
Unionised molecules, molecules which are neutral,
find it easier to cross through the cell membrane.
The cell membrane, if you recall, is effectively
a phospholipid bilayer. It is, to all intents
and purposes, lipophilic. And to penetrate
through the cell membrane, it is often the case
that you need neutral molecules for passive
diffusion to be successful.
Ionisable groups can actually be masked. Going
back to what we said before, for example,
converting a carboxylic acid into an ester,
as in the case of a number of prodrugs that
we’ll come on to in the next lecture. However,
other factors also affect the amount of active
drug being absorbed.
Acid sensitivity, which we’ll see in a second,
can be a major problem for some drugs and
will have a dramatic effect on the amount
of active drug absorbed.