Variability due to genetic differences

Question 1

What types of inheritance are associated with the different metaboliser types?

Answer 1

aa - autosomal recessive - poor metaboliser
Aa - Intermediate
AA - Extensive

Question 2

What’s an example of a null function enzyme? What effect does this on the drug that this enzyme eliminates?

Answer 2

Omeprazol: Na/K ATPase inhibitor. reduce stomach acid secretion as part of treatment for peptic ulcer disease GERD.

The major route of clearance of omeprazol is hepatic clearance by CYP2C19 enzyme.

Individuals who have inherited two variant copies of null function CYP2C19 will be poor metabolisers of omeprazole. Plasma levels will be elevated due to decreased hepatic clearance.

Question 3

How can poor metabolisers be detected?

Answer 3

Plasma concentrations of the drug.

Measuring the ratio of the drug/metabolite in the plasma
High - Poor metaboliser
Low - Extensive metaboliser

Question 4

What is clopidogrel used for and what enzyme is it bioactivated by? What are the risks with the different alleles?

Answer 4

It’s used in anti platelet therapy (combined with aspirin) after percutaneous coronary stent to minimise the risk of further ischemia due to thrombosis.

It is a pro drug that is bioactivated by CYP2C19.

1/1 normal
17/17 “high normal” activation - could have excessive bleeding - give them a smaller dose.
2/2 - increased risk of stent thrombosis - consider another drug.

Question 5

Give an example of an enzyme where gene duplication or deletion and/or SNP occur, and how does this affect the metabolism?

What drug does this enzyme convert?

Answer 5

CYP2D6.

Duplication - 3/4 copies are ultra-metabolisers
Deletion, SNP - no function - Individual with no functional alleles i.e. a combination of SNPs or deletion are POOR METABOLISERS.

• The analgesic properties of codeine requires its conversion to morphine
• Morphine has a 200-fold higher affinity for mu-opioid receptors
• Morphine 6-G is also active at these receptors
• Several ways of eliminating codeine and morphine from the body (not just 2D6 is involved)
• Can’t form morphine if you don’t have 2D6
• If UM may form higher levels of morphine

Question 6

What’s an example of an gene where insertion mutation affects the metabolism of the patient?

What drug is associated with this enzyme and how is it affected by the mutation?

Answer 6

UGT1A1 gene - where there is an extra TA inserted, *28. This variant decreases transcription by 75% i.e. 25% less enzyme. Homozygous variant 50% less enzyme compared to 1/1 individuals.

The drug SN-38 is cleared by this enzyme. 128 has 80% clearance, 2828 has 62% clearance. The chance of toxicity is increased. SN-38 is a potent inhibitor of DNA tropoisomerase and is cytotoxic. It has a very narrow therapeutic window.

So there are different tolerated doses for the different groups.