Pharmacogenomics

Question 1

describe factors that contribute to individual variation in drug response

Answer 1

Intrinsic
- sex, pregnancy, age, disease, genetics,
extrinsic
- drug interactions, environment, diet, smoking

Question 2

describe single nucleotide polymorphism

Answer 2

single nucleotide polymorphism - substitution of one nucleotide with another

With a prevalence of greater the 1% within a population

Question 3

Describe the impact of polymorphism in the coding and regulatory regions of genes on target proteins

Answer 3

regulate transcription
* amount of mRNA and protein
determine amino acid sequence
* protein activity
regulate mRNA translation/stability
* amount of protein

Question 4

Impact of SNP on NAT-2 in TB patients

Answer 4

isoniazid is an anti-TB drug that is inactivated by acetylation via NAT-2’

If NAT-2 is hyperactive the drug will inactivate too quickly and have little therapeutic effect

If NAT-2 isn’t acetylated fast enough is will cause toxicity to liver and peripheral neuropathy

Question 5

describe the metabolism of azathioprine

Answer 5

azathioprine is a prodrug that is rapidly metabolised to 6-mercaptopurine and then 3 metabolites
- thiouric acid (inactive) (via xanthine oxidase)
- S-methyl-6-mercaptopurine
(inactive) is metabolised by TPMT
- 6-thioguanine nucleotide (active) is metabolised through regulatory pathways

Question 6

Describe the clinical use of azathioprine

Answer 6

Impairs DNA synthesis in leukocytes
✔ stops production of malignant
leukocytes → childhood leukaemia
✔ reduces production of normal
leukocytes → inflammatory bowel disease
✔ fewer leukocytes to mediate
transplant rejection (old use)
✖ too much stops production of normal
leukocytes → cannot fight infection

Question 7

describe the clinical relevance of single
nucleotide polymorphism of thiopurine-S-methyltransferase

Answer 7

Low TPMT activity in individuals increases the regulatory metabolism of azathioprine increasing the levels of 6-thioguanine nucleotide leading to potentially adverse effects

Question 8

describe the clinical importance of pharmacogenomics

Answer 8

predicting drug overdose
preventing adverse drug reactions e.g abacavir
Improving drug efficiency
Predicting the activation of prodrugs e.g Codeine
Developing targetted drugs for cancer chemotherapy
Enabling drug development and discovery

Question 9

describe the challenges associated with
implementation into clinical practice

Answer 9

challenges
* a perceived lack of clinical utility
* inability to access genotyping tests
* lack of clarity on cost-effectiveness
* lack of knowledge on how to interpret pharmacogenomic tests
* worries about disruption to the normal clinical pathway
* concerns over confidentiality issues