Drug metabolism Flashcards
How is the balance between lipid-soluble and water-soluble managed when creating drugs?
You need the drug to be lipophilic to access tissues and cross barriers but they also need to be soluble so that they can stay in the blood and be delivered to excretion sites.
It is general practice to take lipid-soluble drugs and all the body to alter (produce a metabolite) them to water-soluble so they can be excreted.
What are the 2 phases of drug metabolism?
- Main aim is to introduce a reactive group to the drug
- Main aim to add a water-soluble conjugate to the reactive group
what sort of reactions happen in phase 1 metabolism?
Oxidation/ reduction reactions (to add functional groups)
Or hydrolysis reactions (unmasking the reactive group).
Generally, drugs either get a hydroxy group added by hydrolysis/reduction or oxidised
What is the end result of phase 1 metabolism?
- Oxidation leads to the production of electrophiles
- Hydrolysis/ reduction leads to nucleophiles
Where does phase 1 metabolism take place?
Liver
Which enzymes are important for metabolism?
(different subtypes of) Cytochrome p450
We all have different levels of thee cytochromes (very unique). It is hard to predict how one person is going to handle that drug. If the cytochrome for one person is low, they will not metabolise that drug very well.
In humans, there are 57 subtypes of cytochrome p450 and these enzymes are predominantly found in the liver.
how can you tell if it is a hydrolysis reaction?
There will be an addition of water
And the product will be broken down
problems which arise after phase 1 metabolism
The active parent drug can go on to produce an inert metabolite but equally it can produce an active metabolite (which prolongs the effect of the drug)
How can phase 1 be useful?
Inactive parent drugs can undergo phase 1 and become activated (e.g. codeine, which is metabolised to morphine). These drugs are called prodrugs which need metabolism to activate them.
What is phase 2 metabolism?
Adding big polar groups to make the compound more soluble- there are only a few discrete reactions that can happen for phase 2 metabolism
what is phase 2 metabolism for electrophiles?
Glutathione conjugation
this needs glutathione agent
What are the possible phase 2 metabolism pathways for nucleophiles produced in phase 1 metabolism?
- Glucoronidation: conjugating agent is UDP-glucuronic acid
- Acetylation: conjugating agent is acetyl CoA
- Sulfation: conjugation agent is 3’ phosphoadenosine- 5’- phosphosulphate
What is the metabolic pathway for aspirin?
It is hydroxylated in phase 1 (undergoes hydrolysis). It then undergoes glucuronidation. It is a low affinity/ high capacity process- more likely to occur at high dosages.
What is the metabolism of paracetamol?
Uses sulfation- high affinity, low capacity. Not a lot of it but it is a very effective process. As the dose of paracetamol increases, it switches to glucuronidation.
A small amount of paracetamol is metabolised differently.
Paracetamol converts to an electrophile in phase 1. The electrophile is called NAPQI. They are really reactive. Then in phase 2, it is converted into an electrophilic conjugate.
What happens in paracetamol overdose?
In paracetamol overdose, you use up the glutathione store, therefore a lot of the reactive NAPQI electrophiles are produced. This can lead to liver damage and dysfunction.
Helpful spider diagram for phase 2 metabolism
