Prodrugs

Question 1

List 5 advantages of prodrugs

Answer 1

1. ) Avoid first pass metabolism - increased bioavailability
2. ) Increased tissue permeation through altering log P
3. ) Decreased side effects by targeting the release of the prodrug to the target organ
4. ) altered pharmacokinetics e.g. increased duration of action
5. ) Better pharmaceutic properties e.g. better taste

Question 2

List 5 disadvantages of pro drugs

Answer 2

1. ) More complex = more to worry about
2. ) Interspecies metabolism variability
3. ) Possible chemical instability upon storage
4. ) Possible toxicity of the prodrug moiety
5. ) More expensive

Question 3

Name 3 non-polar functional groups

Answer 3

1. ) alkyls/aryls
2. ) Halogens
3. ) Ethers

Question 4

When measuring Log P, Octanol isn’t a perfect model for a cell membrane. What other solvents have been used, particularly for CNS acting drugs (that have to cross the BBB)

Answer 4

Cyclohexane

Question 5

How does pH affect LogP?

Answer 5

If a drug is ionisable, depending on the pH it might become ionized. An ionized drug will have a much lower logP = will be more polar.
(When measuring LogP, could put a buffer of physiological pH in the place of water)

Question 6

What does a logP of -1 mean?

Answer 6

The drug is x10 more soluble in the aqueous phase than in the organic phase

Question 7

Why do we need a balance between hydrophilic and lipophillic properties i.e. a logP that neither too high or too low?

Answer 7

If P is low, passive diffusion will be slow and drug action limited
If P is too high the majority of the drug will reside in the lipid phase - far from the site of action. It will also lead to poor water solubility = complicated dosing
A lipophilic drug will also show less selectivity towards proteins

Question 8

What are the 3 approaches to improving target tissue delivery?

Answer 8

1. ) Pharmaceutical technologies
2. ) Analogue synthesis
3. ) Prodrug synthesis

Question 9

Most prodrug are derived from carboxylic acids. We hide the carboxylic group (or OH) by replacing the H with an alkyl chain to make an ester. Why does hiding the COOH group improve drug delivery?

Answer 9

It increases the lipophilicity (logP) of the drug and so increases it bioavailability

Question 10

What enzyme is needed to cleave an ester prodrug?

Answer 10

Esterase

Question 11

Why are ester prodrugs popular?

Answer 11

Easy to prepare, chemically stable, pro-drug moiety is non-toxic

Question 12

Why is salicylic acid administered as its pro-drug aspirin?

Answer 12

To reduce gastric irritation

(Ester is formed on the alcohol

Question 13

How can sustained drug delivery at the brain be achieved?

Answer 13

Pharmaceutical technologies or prodrugs can be formulated that are lipophillic enough to cross the BBB but once there are metabolised via oxidation or esterase into active polar drugs that cannot cross back across the BBB.

Question 14

Why are amide pro-drugs less popular than ester prodrugs?

Answer 14

Because the rate of hydrolysis of amides in vivo is very slow. CONH&raquo_space; NH2

Question 15

Pro-drugs that are activated by oxidation/reduction are also popular.
1.) Me-S=O&raquo_space; Me-S
2.) N-Me&raquo_space; N+-Me
Are these reactions oxidation or reduction and how would the prodrugs improve properties?

Answer 15

1.) Loss of o2 = reduction
The prodrug improves drug water solubility
2.)Loss of electrons = oxidiation
Vastly improves BBB permeation and can get stuck in brain once charged

Question 16

What are the 4 requirements for site specific delivery of pro-drugs?

Answer 16

1. ) Rapid uptake at site of action
2. ) No cleavage of pro-drug moiety at liver or kidney (unless this is the site of action)
3. ) Efficient cleavage at site of action
4. ) Retention of drug at active site for a reasonable amount of time

Question 17

How do we ensure that the pro-drug moiety can only be cleaved at site of action?

Answer 17

Design a pro-drug that can only be cleaved by enzyme that is specific to target organ
E.g. dopamine has vasodilating effects in the liver that would be useful in treatment of shock = designed prodrug that is cleaved by GLUTAMYL DOPAMINE = drg is concentrated in the liver

Question 18

Explain how antibody directed enzyme pro-drug therapy works

Answer 18

1. ) Find an antibody that is specific for target e.g. expressed on the membrane of a tumor cell
2. ) Find an enzyme that is selective for the antibody
3. ) Administer a pro-drug that need this enzyme to be cleaved = site specific delivery

Question 19

What group of drugs could be called prodrugs due to the need for the addition of 3 phosphate groups to the OH gorup in order for them to become activated?

Answer 19

Anti-viral Nucleoside analogues e.g. AZT (AIDS) becomes AZT-triphosphate
Same for anti-cancer nucleoside analogues

Question 20

What enzymes re in charge of phosphorylation?

Answer 20

Kinases

Question 21

Why do nucleoside analogues have to be triphosphates in order to be active?

Answer 21

Have to be triphosphates in order to be able to incorporate into DNA

Question 22

List 3 problems of nucleoside analogues:

Answer 22

1. ) Poor metabolism into the active form - have to be phosphorylated 3 times = kinases will notice that the molecule is foreign and might deactivate it
2. ) Clinical toxicities - bind to DNA and kill cell = good if selective for diseased cells but otherwise will cause damage
3. ) Emergence of resistant tumors/viruses - if take drug for a long time, the trasporter in charge of active transport into the cell may become mutated = poor drug uptake

Question 23

Why can’t we administer the nucleoside analogues as monophosphates?

Answer 23

1. ) Would be to hydrophillic (all the O2 groups + would be inoized at phys pH) and wouldn’t pass cemm membrane
2. ) Phosphate groups are unstable = would be de-phosphorylated before reaching site of action

Question 24

What is the solution for the successful administration of nucleoside analogues?

Answer 24

Administer as a monophosphate but mask the 2 OH groups so that the drug isn’t ionisable = passes membrane. Once it has crossed the membrane we want enzymes to cleave the groups and release the active form.
e.g. mask 1 OH with a benzene ring and the second with an amino acid ester - technology developed at redwood