In the previous lectures, we looked at enzyme
inhibition, biological interactions, but just
as important - the pharmacokinetic and pharmacodynamic
profiles for different types of drugs and
those factors which influence them.
Specifically, when it comes to, for example,
the pharmacokinetics, we were concerned with
how lipophilicity can often lead to an enhanced
first pass effect with metabolism, decreasing
the amount of bioavailable drug. However,
sometimes as we’ll see in this lecture, it
can be used to our advantage in converting
prodrugs into active drugs.
So, let’s just recap about what a prodrug
is. A prodrug can be defined as a compound
which is inactive when administered, but gets
converted to... in the body to the active
form through biotransformation. This can be
mediated enzymatically by those endogenous
Prodrugs are usually produced by the attachment
of an active drug to something known as a
promoiety through a metabolically-labile linkage.
The term promoiety may sound a little bit
complicated, but the reality is, if we were
talking about, say, a carboxylic acid active
drug then a promoiety would may just be an
alcohol that we would attach to it as an ester.
This ester, as you know, is a metabolically-labile
linkage, which can be hydrolysed by esterases
which is systemic.
The prodrug must be readily converted in the
body to the active form and also, the promoiety
itself must not be toxic. Produgs themselves
depend on endogenous enzymes to transform
them to the active species and are used for
many purposes including to increase absorption
also or to decrease the number of side effects.
So, let’s have a look at the factor of increasing
lipophilicity. Some drugs have low lipophilicity,
can lead to poor oral bioavailability. This
is by virtue of them having poor oral absorption
and absorption through the gastrointestinal
Produgs can be synthesised, whereby a lipophillic
group is added to the active drug to increase
its overall lipophilicity. So, let’s have
a look at a specific example of this. Famiciclovir
is a prodrug of this compound here, Penciclovir.
Penciclovir is a DNA polymerase inhibitor
used as an anti-viral to, for example, treat
DNA viruses; an example being the herpes simplex
and also, cytomegalovirus.
Problem is though, Penciclovir is not particularly
orally bioavailable. Note the polarity here
- we have two 3OH groups, the OH groups, whilst
enhancing water solubility, do nothing to
help it pass through the gastrointestinal
tract. By modifying those alcohol OH groups
and converting them into ester groups such
as in the case of Famciclovir, we have created
a produg, a prodrug which has far better oral
and gastrointestinal absorption, thus resulting
in increased bioavailability of the Famciclovir
which goes on to be hydrolysed and then further
oxidised by an aldehyde oxidase to the Penciclovir