Drug Metabolism By The Liver Flashcards
What is phase 1 of metabolism?
Catabolic process that breaks a drug down into a more simpler form. This makes the drug more reactive.
What is phase 2 of metabolism?
Conjugation (anabolic process) that makes a drug more water soluble = more polar.
Why is it important to make a drug more water soluble?
Because the most common route of excretion is via urine. More can be excreted by the renal route if it’s water soluble.
What is cytochrome P450?
It’s a group of enzymes
What are microsomes mixed function oxidises?
Important group of enzymes involved in phase 1 metabolism.
What do microsomes mixed function oxidases require?
They require oxidase substrate, NADH, NA DH- P450 reductase and molecular oxygen
Why is drug metabolism important?
It makes a drug more polar and increases solubility so it can be excreted via the urine.
Where are microsomal mixed function oxidases found?
Embedded in the lipid membranes.
In the endoplasmic reticulum.
The cytochrome P450 cycle?
Allows for recycling of cytochrome P450 and the generation of an oxidised derivative of the drug.
What type of reaction is a phase 1 reaction?
Catabolic
How would you expect omeprazole to affect the action of clopidogrel?
Make it less effective.
Clopidogrel produces an active metabolite CYP2C19, this is inhibited by omeprazole. Less active metabolites will be formed so clopidogrel is less effective.
Clinically this means that a patient is more likely to suffer from a blood clot (thrombus)
What is the benefit of administering enalaprilat as the prodrug enalapril?
Enalapril is better absorbed from the GI tract than enalaprilat, so more of the drug will reach its target.
What are the steps in the cytochrome P450 cycle?
Start = P450 is binded to iron. Drug complex formed = Fe3+ DH Fe03+ = oxidised version Cytochrome P450 is recycled, the cycle starts again. Drug oxidation = Cytochrome P450 cycle
What is clopidogrel?
Used to treat vascular ischaemia. Anti-platelet drug.
Give an example of enzyme inhibition on drug metabolism.
Clopidogrel and omeprazole.
clopidogrel can irritate the GI tract lining.
omeprazole is a PPI used to treat gastric ulcers.
omeprazole inhibits the active metabolite CYP2C19, so at any given dose there will be a lower amount of active metabolite formed = less anti-platelet action
what active metabolite is induced by clopidogrel?
CYP2C19, this is responsible for the anti-platelet action.
what effect does omeprazole have?
Proton pump inhibitor, it inhibits the active metabolite CYP2C19
What is the most common phase 2 reaction
glucuronidation; attaches endogenous compound to N, O and S atoms
What is a Prodrug?
Its generally an inactive form of the drug, it needs to be activated by liver enzymes to produce an active metabolite.
Give an example of a prodrug;
steroids can be administered this way.
for example enalapril is converted to enalaprilat by the liver.
Enalaprilat is potent in its active form.
Why is enalaprilat not administered as an active drug?
because its not easily absorbed into the body.
the inactive form enalapril is better absorbed
what are the therapeutic advantages of active metabolites?
its actions can be prolonged for example diazepam is converted to oxazepam
what happens in paracetamol overdose?
Phase 2 metabolic pathway becomes saturated so paracetamol goes through phase 1.
this depletes stores of Glutathione.
there is a build up of a toxic intermediate (Covalent binding to liver protein)
this leads to necrosis of cells
What is phase 2 metabolic reactions usually referred to?
Glucuronidation
What do cytochrome p450 enzymes have associated to them?
They have a heme-molecule associated with them as a co-factor
What is the heme group responsible for?
It facilitates binding to the active site. They catalyse phase 1 reactions and are associated with the endoplasmic reticulum.
