CYP450 hell

Question 1

Importance of CYP1A2?

Answer 1

Smoking induces CYP1A2
Substrates of 1A2 are olanzapine and clozapine therefore sudden smoking cessation can result in toxic clozapine and olanzapine levels

Question 2

Genetic polymorphisms relevant to warfarin?

Answer 2

Warfarin has 2 isomers S-warfarin (more potent) and R-warfarin. S-Warfarin is metabolised through 2C9. Some patients lack significant 2C9 activity and get high INRs with low doses.
Other genetic mutation is the VKORC1 polymorphism which gives high INRs at low doses

Question 3

What are common inducers? ( of all CYPs except 2D6)

Answer 3

Rifampicin
Carbamazepine
Phenytoin
St Johns Wort

Question 4

What do inhibitors do to drug levels?

Answer 4

Increase drug level

* Unless pro-drug - will decrease level

Question 5

What do inducers do to drug levels?

Answer 5

Decrease drug level

* Unless pro-drug - will increase level

Question 6

What are key substrates of CYP3A4?

Answer 6

Steroids including inhaled
Cyclosporin/Tacrolimus
Statins
OCP
Benzodiazepines
Carbamazepine

Question 7

What are key inhibitors of CYP3A4?

Answer 7

Protease inhibitors (particularly ritonavir)
Macrolides (erythromycin/clarithromycin)
Azoles
Grapefruit
Verapamil
Diltiazem

Question 8

Describe the polymorphisms seen with CYP2D6 - use codeine as example (pro-drug)

Answer 8

Poor metabolisers

• seen in Asian and white population
• low or absent enzyme activity
• low conversion of codeine to morphine
• inadequate pain relief

Ultra-rapid metabolisers

• seen in African and white population
• increased enzyme activity
• increased metabolism to morphine
• risk of toxicity/overdose

Question 9

Key substrates of CYP2D6

Answer 9

Codeine (pro-drug)
Tamoxifen (pro-drug)
Metoprolol

Question 10

Key inhibitors of CYP2D6

Answer 10

Paroxetine/fluoxetine
Quinidine
Amiodarone