Lecture 9: Variability due to genetics

Question 1

Pharmacogenomics? (PGx)

Answer 1

investigations of variations of DNA and RNA characteristics as related to drug response

Question 2

Pharmacogenetics? (PGt)

Answer 2

A subset of PGx and is defined as the influence of variations in DNA sequence on drug response (clinically relevant)

Question 3

% predictable vs unpredictable variability?

Answer 3

50% predictable - genetic or ennvironmental

50% unpredictable

Question 4

CYP3A5?

Answer 4

marker drug - Tacrolimus

Clinically relevant drug : tacrolimus used as a immunosuppressant eg. kindey trans.

• *1/1 genotype have 2 fold CL
• *3/3 are non-expressors

80% of caucasains and 20% of africans are *3/3

Question 5

N-Acetyl-transferase Acetylation

Answer 5

Marker drug = procainamide

Clinically relevant drugs = procainamide (anti-arrhythmia)

= anti-TB (isonaizid)

• NAT genotype = 50% caucasains, 30% africans 10% asains
• have lower clearance

Question 6

UDP-G

Answer 6

marker drug = bilirubin

hereditary hyperbilirubinaemia = gilberts (3-10% population)

Cliniacally relevant drugs: anti-cancer drug (irinotecan)

• active metaobolite is elimnated by glucuronidation
• gives sever neutropenia and diarrhoea
• 40% african american, 35% caucasains get toxicity

Question 7

Thio-purine-methyl-transferase (important)

Answer 7

marker drug = 6-mercaptopurine

Clinincally relevant drugs:

1. 6-mercaptopurine (for childhood acute lymphocytic leukemia)
2. Azathioprine (pro-drug for 6-MP) -(used for Crohn’s and arthritis)

Severe toxicity (diarrhoea andneutropenia) in TPMT genotypes

• homozygous deficiency 1 in 3000
• heterozygous deficiencey 1/10 (requiring a 10folf dose reduction. Ie 1/10 people is getting avoidable toxicity)

Question 8

Alcohol/acetaldehyde dehydrogenase

Answer 8

marker drug = Ethanol

clinically relevant drugs:

1. recreational ethanol

Alcohol dehydrogenase and aldehyde dehydrogenase

• with fast alchohol and slow aldehyde metabolism you get flushing and with reverse you get high tolerance

Question 9

P-gylco-protein transporter

Answer 9

Multi-drug resistance to treatment -(cancer, rheumatoid arthritis, inflammatory bowel disease, epilepsy)

common mechanism

• increased activity of PGP transporter
• drug absorption decreased
• transport out of brain and tumour increased

Question 10

Oranic anion transporter?

Answer 10

statins are most widely used and effective in NZ

myopathy (rhamdomyolysis, myostitis) occurs in 1/10,000

transporter deficiency leads to decreased clearance and higher bocy concentrations leading to a 60x higher risk of myopathy

Question 11

warfarin sensitivity and resistance

Answer 11

due to genetic differences in VKOR (vitamin k epOxide reductase)

decreased activity in 80% of asain so only require 3mg/day

decreased CYP4F2 activity in 60% of caucasains so require 6mg/day