Prodrugs Flashcards
a drug is
a compound (of known structure) that when administered to a living organism produces a biological effect
a pharmaceutical drug
is used to diagnose , cure , treat or prevent disease
a good drug should -
be specific
have minimal adverse effects
be stable in a range of dosage forms
be acceptable to the patient
a prodrug
is a compound which is administered in an inactive form but is then converted by the organism to the active drug using enzymatic and non enzymatic processes
types of prodrug
carrier linked prodrug
>bipartate
>tripartate
>mutual
bioprecursor
rationale for creating prodrugs
Biopharmaceutical society classified drugs into 4 categories
prodrugs are usually category 2 ( low solubility but high permeability ) or category 3 ( high solubility but low permeability )
increased aqueous solubility
alter absorption and distribution
site specify
prolonged release
toxicity
patient compliance
formulation
altering aqueous solubility
the succinate ester of chloramphenicol has much greater solubility in water than unesterified chloramphenicol
this makes this ester more suitable for iv use
the palmate ester of chloramphenicol has much lower solubility in water than unesterified chloramphenicol
this makes this ester more palatable for oral use ( chloramphenicol has a very bitter taste but the palmitate ester doesn’t dissolve on the tongue , masking the taste )
improving membrane permeability
polar molecules have difficulty crossing the cell membrane .
in prodrug design , we often mask these polar groups through ester formation or N-methylation to produce a more non-polar molecule
the ester or methyl group can be easily removed by enzymes in the blood stream
sometimes simple aliphatic esters hydrolyse too slowly to be useful as prodrugs
we can alter the rate of hydrolysis by introducing electron-withdrawing groups adjacent to the alcohol moiety. the resultant inductive effect stabilises the alcohol , making it a better leaving group.
it is also possible to design a prodrug that can pass through membrane transport proteins. this is sometimes called the Trojan horse approach . an example is levodopa
improving drug targets
prodrugs can be synthesised to contain molecules that are recognised by specific organ systems , allowing a degree of targeting . for example , testosterone undecanoate avoids first pass metabolism by entering the circulation via the lymphatic system
prolonging activity
drugs administered by depot injection are often lipophilic ester prodrugs. these slowly diffuse out of fat tissue into the blood stream where they are then hydrolysed to release the active drug.
for example , haloperidol decanoate
reducing toxicity and side effects
the alkylating agent cyclophosphamide is used in cancer chemotherapy . it is administered as a prodrug which is then activated by the cytochrome P450 system to the active alkylating agent. the by-product can cause significant renal damage ; co-administration of a sulfydryl donor such as N-acetylcysteine or sodium 2-mercaptoethane sultanate can protect the kidneys
various aspirin prodrugs are being investigated to reduce gastric irritation.
pharmacogenomics
the ability to activate a prodrug depends on heavily on the presence of enzymes , which can be freely circulating or found in the cytochrome P450 system. many enzymes exit in different isoforms which arise from single nucleotide polymorphisms . often different isoforms have different kinetic constants and therefore will activate prodrugs differently . other proteins involved in the ADME of drugs can similarly exhibit genetic variation. the detection and study of these differences is known as pharmacogenomics.
example of this is clopidogrel is activated by CYP2C19 . approximately 22.5% of the population of Japan were found to have a polymorphism in CYP2C19 which altered their response to treatment .
example 1 : ace inhibitors
blood pressure is partly controlled by the action of angiotensin converting enzyme which converts angiotensin 1 to angiotensin 2 . Bristol-Myers-Squibb found that a snake venom caused rapid hypotension; this formed the basis for synthesis of a range of drugs now known as ‘ACE inhibitors’.
These compounds interact with ACE through four key regions .Merck developed an alternative dicarboxylic acid ACE inhibitor, enalaprilat, which was found to have very poor oral bioavailability. It was redeveloped as an ethyl ester prodrug, enalapril.The maleate salt of enalapril (Vasotec) is the most popular oral formulation.
The use of a malate salt improves physical stability of enalapril – e.g. lower hygroscopicity and increased compatibility.
Example 2: Antivirals
Most drugs that are active against DNA viruses were originally developed with Herpesviridae family in mind.
These drugs are usually nucleoside analogues that act as chain terminators during viral DNA replication.
To prevent antiviral drugs from interfering with host DNA, they are administered as prodrugs which are selectively activated within viral particles.
One of the first nucleoside analogue antivirals synthesised was aciclovir which is based on deoxyguanosine.
When aciclovir enters infected cells, it undergoes initial phosphorylation by viral thymidine kinase to form aciclovir monophosphate:
Aciclovir monophosphate can be incorporated into viral DNA and act as a chain terminator, but this has a minor contribution to the overall antiviral effect.
The major fate of aciclovir monophosphate is to undergo further phosphorylation by cellular thymidylate kinase to give aciclovir triphosphate
Aciclovir triphosphate can (i) bind to viral DNA polymerase inactivating it; (ii) act as a chain terminator since there is no 3’ OH from which to extend the polynucleotide chain.
Aciclovir has poor oral bioavailability (15 – 30%) and so various ester prodrugs were developed to improve absorption from the GI tract.
For example, valaciclovir is the L-valyl ester of aciclovir which is transported into enterocytes by carrier proteins that recognise the valine moiety.
Example 3: Statins
Epidemiological and mechanistic evidence suggests a link between high cholesterol and cardiovascular disease.
Statins are a group of hypolipidaemic drugs that reduce de novo cholesterol synthesis by blocking the rate-limiting step:
Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors with a portion of their structure resembling the normal product of the reaction (mevalonate).
The first statin (mevastatin) was obtained from the mould Pythium ultimum. This had a lactone (cyclic ester) head group which was hydrolysed in vivo by esterases to give the polar dihydroxyheptanoic acid group:
Lovastatin and simvastatin are the only prodrug statins currently in use (lovastatin is no longer prescribed in the UK).
Metabolism of statins exhibits genetic variation with some individuals at greater risk of developing rhabdomyolysis depending on their expression of the SLCO1B1 gene. Homozygotes for the variant gene are poor metabolisers of simvastatin and carry a much greater risk of serious side effects.
