Prodrugs: Introduction

by Adam Le Gresley, PhD

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    00:02 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 enzymes.

    01:00 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.

    01:24 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.

    01:58 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 tract.

    02:16 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 active ingredient. Reducing ionisation.

    About the Lecture

    The lecture Prodrugs: Introduction by Adam Le Gresley, PhD is from the course Medical Chemistry.

    Included Quiz Questions

    1. A compound, which upon administration in the body in an inactive form gets converted to the active form through transformation reaction catalyzed by endogenous enzymes.
    2. A compound administered in the body in an active form which becomes inactivated through biological transformations.
    3. A compound administered in the body in an active form which is cleaved into small molecules to activate certain enzymatic molecules.
    4. A compound administrated in the body in an active form which is cleaved into small molecules to activate influx of Na ions through cell membranes.
    5. A compound administered in the body in a semi-active form which becomes fully activated after combining with lipids.
    1. ... is attached to a pro-moiety through a metabolically-labile bond.
    2. ... is attached to a pro-moiety through a metabolically-stable bond.
    3. ... is attached to a metal atom through a metabolically-stable bond.
    4. ... is attached to a halogen atom through a metabolically-labile bond.
    5. ... is attached to a transition metal atom through a metabolically-stable bond.
    1. Side effects
    2. Non-toxic nature of pro-moiety
    3. Readily conversion of prodrug to active form
    4. Dependence upon the endogenous enzymes for biotransformation
    5. High absorption rates

    Author of lecture Prodrugs: Introduction

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD

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