Drug metabolism Flashcards
(19 cards)
Why do we want drugs to be lipophilic?
-they can access tissues and have therapeutic effects
Why do we want drugs to be water soluble?
-retained in the blood to deliver to excretion sites
What type of drugs do we use?
- design lipid soluble ones
- the body alters it to become less lipid soluble during the process of excretion
- conversion of drugs to metabolites
What is the main aim of phase I metabolism?
-increase the polarity of the drug by introducing a reactive group
What 3 ways is phase I achieved?
- oxidation (most common)
- reduction
- hydrolysis
How does oxidation/reduction increase polarity?
-creates a new functional group, acts as a point of attachment for phase II reactions
how does hydrolysis increase polarity?
-unmasks a reactive group
Where does metabolism occur and by what enzyme?
mostly the liver by cytochrome P450
List the 3 effects of phase I metabolism
- active parent drug to inert metabolite
- active parent drug to active metabolite
- inactive parent drug to active metabolite
What is the aim of phase II drug metabolism?
-add a water soluble conjugate to the reactive group
What occurs to electrophiles during phase II
glutathione conjugation (R-SG)
What 3 reactions can happen to nucleophiles during phase II?
R-OH =R-GI by Glucuronidation
R-SH = R-Ac by acetylation
R-NH2 = R-SO2H by sulfation
Which pathway is more likely to occur at higher doses?
Glucuronidation - it has a high affinity/low capacity
e.g. aspirin
which pathway is more likely to occur at lower doses?
sulfation- high affinity/low capacity
e.g. paracetamol
How does paracetamol concentration effect the metabolism pathway?
-in low concentration sulfation will occur (60%) but as concentration increases this switches to become glucuronidated )30%)
How is the other 10% of paracetamol metabolised?
glutathione conjugation
How does paracetamol undergo glutathione conjugation
- oxidised to NAPQI, a very powerful electrophile
- if there is an overdose all the stores of glutathione are used up then this very reactive electrophile is left in the body, leading to problems
WHat compounds does acetylation usually occur with?
R-OH
R-NH2
R-SH
R is usually an aromatic amine
WHat other reactions can occur during phase 2 which are a lot rarer?
Methylation
Amino acid conjugation
-2 reactions possible with an amino group of AA or carboxylic acid group of AA
