00:01
Another thing you can do by modifying the
structure of a drug is prolong the duration
of action. This is being carried out successfully
for depot injections of steroids and antipsychotics
and usually consists of, for example, ester
derivatives, yet again.
00:16
Let’s have a look, for example, at oestradiol.
So, oestradiol is shown at the bottom right
hand corner here, which is a steroid, as you
can clearly see from its structure and the
prodrug of oestradiol is a ester of that particular
cyclopentanol system in the right hand corner,
as you can see.
So, the prodrug of oestradiol, which is now
more lipophilic, is given intramuscularly
and is hydrolysed slowly, in vivo, to give
the free oestradiol over a prolonged period
of time. And it’s important to know that
whereas when we have relatively short chain
esters, they are quite prone to hydrolysis.
00:56
If we make the chains of the ester look a
bit longer, such as in this case, which is
a pentyl ester, the actual rate of hydrolysis
is actually reduced. So, in this case, rather
than, if you like, quickly clearing or making
available a large amount of active drug through
the actions of esterases, we can actually
release it slowly as a consequence. Another
example would be fluphenazine decanoate,
which has a duration of four
weeks and is given by oily injection.
Now, I would like to come on to another subject
which relates to altered derivatisation and
patient compliance. Prodrugs can also be used
to make a drug more acceptable to take. It
is particularly important when dealing, for
example, with children. So, for example, if
the drug has an unpleasant taste; an example
of this would be, especially in the third
world, a very important antibiotic,
chloramphenicol.
So, clindamycin and chloramphenicol both have
very bitter tastes. This can be overcome by
esterifying them with a long chain fatty acid
such as a palmitic acid. The palmitate ester
has been found to have no bitter taste due
to the reduced aqueous solubility and therefore,
does not dissolve on the tongue. Palmitate
esters are then rapidly hydrolysed to produce
the parent drug once it’s passed through into
the gastrointestinal tract.
Another reason of why prodrugs are important
is that they can be used or modifications
can be used to prevent unpleasant side effects
produced by the parent drug itself. A good
example of this again relates to the inflammatory
cascade, COX-1, COX-2 inhibition. An example
of this would be nonsteroidal anti-inflammatory
drugs or NSAIDs. NSAIDs, and aspirin falls
into that category, can produce gastric irritation
via direct acidic irritation and also via
direct inhibition of prostaglandin production
in the gastrointestinal tract. This is the
problem, particularly if you are trying to
use it over a long term. Prodrugs of nonsteroidal
anti-inflammatory drugs such as nabumetone
can cause minimal irritation; as a prodrug,
they themselves are not acidic. You will see
what I mean in the right hand corner here.
So, nabumetone in the top right hand corner
is, of itself, not acidic; it doesn’t contain
a carboxylic acid group and therefore, can
neither directly antagonise the amounts of
prostaglandin synthase within the stomach
lining nor can it directly irritate as an
acid.
03:37
However, it is actively metabolised in the
liver via an oxidase to the active metabolite
shown in the bottom right hand corner in this
particular scenario. And so, prodrugs of these
NSAIDs such as nabumetone cause minimal irritation
since they are themselves neither acidic nor
antagonists of cyclooxygenase enzymes. As
you can see in the bottom right hand corner
through series of oxidation reactions, the
active metabolite is produced.
04:05
So, in summary, prodrugs themselves are inactive
compounds that are metabolised to the active
compound in vivo using endogenous enzymes.
They are used for a wide variety of different
purposes such as increasing absorption, reducing
side effects and improving distribution and
producing a prolonged release of the active
drug. Ideally, prodrugs should have improved
bioavailability, more so than the parent drug,
and produce non-toxic metabolites.