Drug Metabolism By The Liver

Question 1

What is phase 1 of metabolism?

Answer 1

Catabolic process that breaks a drug down into a more simpler form. This makes the drug more reactive.

Question 2

What is phase 2 of metabolism?

Answer 2

Conjugation (anabolic process) that makes a drug more water soluble = more polar.

Question 3

Why is it important to make a drug more water soluble?

Answer 3

Because the most common route of excretion is via urine. More can be excreted by the renal route if it’s water soluble.

Question 4

What is cytochrome P450?

Answer 4

It’s a group of enzymes

Question 5

What are microsomes mixed function oxidises?

Answer 5

Important group of enzymes involved in phase 1 metabolism.

Question 6

What do microsomes mixed function oxidases require?

Answer 6

They require oxidase substrate, NADH, NA DH- P450 reductase and molecular oxygen

Question 7

Why is drug metabolism important?

Answer 7

It makes a drug more polar and increases solubility so it can be excreted via the urine.

Question 8

Where are microsomal mixed function oxidases found?

Answer 8

Embedded in the lipid membranes.

In the endoplasmic reticulum.

Question 9

The cytochrome P450 cycle?

Answer 9

Allows for recycling of cytochrome P450 and the generation of an oxidised derivative of the drug.

Question 10

What type of reaction is a phase 1 reaction?

Answer 10

Catabolic

Question 11

How would you expect omeprazole to affect the action of clopidogrel?

Answer 11

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)

Question 12

What is the benefit of administering enalaprilat as the prodrug enalapril?

Answer 12

Enalapril is better absorbed from the GI tract than enalaprilat, so more of the drug will reach its target.

Question 13

What are the steps in the cytochrome P450 cycle?

Answer 13

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

Question 14

What is clopidogrel?

Answer 14

Used to treat vascular ischaemia. Anti-platelet drug.

Question 15

Give an example of enzyme inhibition on drug metabolism.

Answer 15

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

Question 16

what active metabolite is induced by clopidogrel?

Answer 16

CYP2C19, this is responsible for the anti-platelet action.

Question 17

what effect does omeprazole have?

Answer 17

Proton pump inhibitor, it inhibits the active metabolite CYP2C19

Question 18

What is the most common phase 2 reaction

Answer 18

glucuronidation; attaches endogenous compound to N, O and S atoms

Question 19

What is a Prodrug?

Answer 19

Its generally an inactive form of the drug, it needs to be activated by liver enzymes to produce an active metabolite.

Question 20

Give an example of a prodrug;

Answer 20

steroids can be administered this way.
for example enalapril is converted to enalaprilat by the liver.
Enalaprilat is potent in its active form.

Question 21

Why is enalaprilat not administered as an active drug?

Answer 21

because its not easily absorbed into the body.

the inactive form enalapril is better absorbed

Question 22

what are the therapeutic advantages of active metabolites?

Answer 22

its actions can be prolonged for example diazepam is converted to oxazepam

Question 23

what happens in paracetamol overdose?

Answer 23

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

Question 24

What is phase 2 metabolic reactions usually referred to?

Answer 24

Glucuronidation

Question 25

What do cytochrome p450 enzymes have associated to them?

Answer 25

They have a heme-molecule associated with them as a co-factor

Question 26

What is the heme group responsible for?

Answer 26

It facilitates binding to the active site. They catalyse phase 1 reactions and are associated with the endoplasmic reticulum.