Class notes
Prodrugs
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Lecture notes on Prodrugs in the Protein Science module of Drug Metabolism.
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Prodrugs- What is a prodrug? It is a pharmacologically medication or compound that after the
intake is metabolised into an active drug. Instead of administering a drug directly, a
corresponding prodrug can be used to improve how the drug is absorbed,
distributed, metabolised, and excreted (ADME).
- How to increase the lifespan of a drug? Remove readily catalysed functional groups
or Pro-Drug (prodrugs ae inactive but are converted to an active drug inside.
- Prodrug-activating enzymes: They are used to create the parent active drug like
esterases and amidases.
- Prodrug role in improving membrane permeability (Ester example) : If a carboxylic
acid is important for drug binding to its target , but It prevents the drug from
crossing a membrane , temporarily “hide” it as an
ester. Once in the blood, it is hydrolysed to the
active form by esterases. This is needed to for
increasing the permeability making It more
effective – we want it to be permeable at first then
after a while the metabolism in the liver can follow
like we saw last lecture so that the membrane permeability would decrease.
- Another way to increase the membrane permeability? N methylation, this is a
common liver metabolic reaction, amines may be methylated to but not the same as
conjugation because conjugation just means increasing the mW, so membrane
permeability is not possible then.
- Another way to increase the membrane permeability? Use of membrane
transporters, there has always been a problem of the drugs being specific to the
transporters, but we can change this by mimicking the structure of the drug
compound so that it mimics the substrate for the membrane
protein.
- What is the prodrug of dopamine? Levodopa. This prodrug Is an
amino acid and can be crossed membrane by carrier protein. Once
across, a decarboxylase (so this is an example of the prodrug-
activating enzyme) removes the carboxyl group and generates dopamine. This is all
because dopamine is so polar.
- What is aspirin? It is a prodrug. It is the prodrug for salicylic acid.
- Aspirin used to reduce toxicity as one of the characteristics of prodrugs: Salicylic
acid is a painkiller., but the phenolic -OH causes gastric bleeding. Aspirin as an ester
to mask this toxic group until it is hydrolysed to salicylic acid. This hydrolysis can be
termed as phase 1 drug metabolism. Then after phase 2 metabolism where the
conjugation happens.
- Biopharmaceutical classification system (BCS): Drugs are based on solubility and
permeability measures. You can use prodrugs to increase solubility or increase
permeability. Class 2 or class3 drugs are changed.
- What does solubility mean? Volume required to dissolve the highest dose.
Bioavailability is required here. Prodrugs increase solubility by adding polar
moieties.
- Prodrugs are often designed to improve bioavailability: Bioavailability means the
concentration of the drug reaching in the bloodstream. We do not want this too low
since it means that that the metabolism to inactive form can happen if it is an active
, drug. Prodrugs are often designed so that it is not poorly absorbed from the
gastrointestinal tract.
Summary: Prodrugs help increase membrane permeability (in that way it improves the
effectiveness), reducing toxicity, making the molecule more soluble thus increasing the
bioavailability. We want membrane permeability then after detoxification can happen
in the liver, but with drugs we want them to cross the membranes to do the work. The
liver can alter it afterwards like we saw in the last lecture.
Improved aqueous solubility helping with bioavailability: Prodrugs can help to
overcome the solubility limitations of poorly soluble drugs when first pass metabolism
is low to moderate and not the main cause of systemic drug availability. Adding a polar
group like phosphate is one of the ways to go about this.
Types of prodrugs:
- Prodrugs are simple chemical
derivatives that require only
one to two chemical or
enzymatic transformation
steps to yield the active parent
drug.
- There is a difference between
the carrier-link prodrug and
the Bio precursor. The carrier-linked prodrug means that you are just masking the
active form with a promoeity so that the activity reduces, and the reverse of the
masking happens later. In the case of Bio precursors, they are different from the
active parent and the prodrug undergoes chemical transformation to get into the
active form.
Ideal drug carrier – what is it, why is it important to use?
- Drug delivery – membrane permeability.
- You want it to be biodegradable, biochemically inert and nonimmunogenic.
- Chemically and biochemically stable in dosage form.
Carrier Linked prodrugs:
- Contains an active drug linked to a carrier group (generally esters or amides) that
can be removed via hydrolytic cleavage. In the carrier-linked prodrugs, the
active molecule (the drug) is temporary linked to a carrier (also known as
a promoiety
- Esters Prodrugs why? Drug molecules which contain alcohols or carboxylic acids are
esterified to give ester prodrugs. When it is esterified, it means that it is less polar
and can cross the membrane, so it helps to increase the membrane permeability.
- Esterases: hydrolase enzymes. These are abundant in the cell which helps to liberate
the active form of the drug.
- Aliphatic esters vs phosphate ester’s different function: Aliphatic esters help to
increase the lipid solubility meaning – membrane permeability. Phosphate esters –
improve the aqueous solubility so that helps with the bioavailability.
- The properties of the carrier group: Biochemically inert, non-toxic
- The bond must be labile meaning: That the bond must be easy to hydrolyse.
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