L.10 Genetic Variability in drug metabolism

Question 1

What are the 4 drug metaboliser phenotypes, which is the reference normal trait and how do they relate to each other inherited wise

Answer 1

Poor metaboliser , intermediate metaboliser, extensive metaboliser (reference normal trait) and Ultra rapid metaboliser.
PM is autosomal recessively inherited and is co dominant with EM, with IM being a heterozygous combo. URM codes for a protein with higher activity than normal or there are more copies of the gene

Question 2

What does the * gene mean

Answer 2

• indicates the allelic form of that gene which *1 being the wildtype. They are number in chronological order, and this allelic type can be due to in/del/SNPs

Question 3

What is the Poor metaboliser trait and what is the risk of that

Answer 3

Inherited loss of function of a drug metabolising enzyme

- could have high levels of drug in blood bc no break down and increased risk of adverse reaction (compared to normal)

Question 4

What is the metabolic ratio and what does it mean

Answer 4

It is the ratio of drug: metabolite plasma concentration.
A high ratio= PM, Low= EM.
The frequency of distribution of metabolic ratio in a population can detect a bimodal distribution.

Question 5

What can you do to counter genetic variation in the enzyme for a prodrug - URM, PM

Answer 5

You can decrease the dose for URM,

You can use alternative drugs that don’t require metabolism by that enzyme for PM.

Question 6

What is wrong with finding the maximum tolerated dose of a drug in patients with unknown clearance enzyme

Answer 6

Surveying the entire population, the PMs will have influenced the safe dose for whole population so patients not carrying the non functional allele may be underdosed- below effective dose

Question 7

How is genotype directed dosing done

Answer 7

All patients are started at a dose and then dose is escalated at next treatment to identify the maximum tolerated dose (dose at which they get adverse effect) for each genotype.

Question 8

When should the role of pharmacogenetic variability be considered

Answer 8

More important if hepatic clearance the major route of elimination and
Have less routes/ viable enzymes for elimination
If it is a prodrug vs normal drug, the effect will be different including the risks
More risk if a narrow therapeutic index compared to wide

Question 9

What other factors can change the metabolising rate of the enzyme even if it doesn’t have a SNP

Answer 9

• Genes can be switched on or off/ upregulated down regulated due to gene-environment interactions such as xenobiotics, hormones, cytokines,