Pharmacogenomics

Question 1

What is the downside to having narrow therapeutic index drugs?

Answer 1

It would be easy to go beyong minimum toxic concentrations

Question 2

What is pharmacogenomics?

Answer 2

(PGx) is defined as the study of variations of DNA and RNA characteristics as related to drug response.

Question 3

Explain how genetic variation can affect drug response?

Question 4

Explain how genetic variation can affect metabolism of a drug.

Question 5

What is pharmacogenetics (PGt)?

Answer 5

It is the study of variations in DNA sequences as related to drug response.

Question 6

What is the difference between pharmacogenomics and pharmacogenetics?

Answer 6

PGx is studying the DNA and RNA characteristics, while PGt studies the sequence of DNA variation.

Question 7

What is Single Nucleotide polymorphism (SNP)?

Answer 7

Substitution of one DNA unit for another at a particular site, resulting in an altered amino acid in the protein synthesis.

Question 8

What is DNA Insertion?

Answer 8

Intrusion of an additional DNA unit or units into the gene sequence, which may or may not change the sequence of the triplet in which it occurs, but all subsequent triplets produce alterations in many amino acids, as there is a frameshift mutation

Question 9

What does Warfarin inhibit?

Answer 9

Vitamin K oxidoreductase

Question 10

What gene variant causes individuals to not metabolise warfarin as fast?

Answer 10

CYP2C9 variants because S-warfarin is metabolised primarily by CYP2C9.

Question 11

What gene catalyse vitamin K epoxide reductase (VKOR)?

Answer 11

VKORC1 - which increase sensitivity to warfarin and lower dose requirements

Question 12

What drugs target epidermal growth factor receptor (EGFR) mutations?

Answer 12

Gefitinib and erlotinib

Question 13

What specific region of the EGFR does gefitinib bind to?

Answer 13

The ATP cleft to inhibit EGFR activation

Question 14

What are the EGFR pharmacogenomics mutations?

Answer 14

K-Ras mutation
PTEN loss
PIK3CA mutation
BRAF mutation and many more

Question 15

What is irinotecan (CPT-11) used for?

Answer 15

It is used for cancer chemotherapy because it is able to inhibit topoisomerase I

Question 16

How does irinotecan hinder DNA replication and transcription?

Answer 16

It inhibits topoisomerase I, which prevents supercoiled DNA from relaxing, hence unable to remove helical constraints that can hinder DNA replication and transcription.

Question 17

What Phase I metabolism does irinotecan undergo?

Answer 17

Irinotecan is a prodrug that undergoes phase I metabolism in the liver by carboxylesterase to form its active metabolite SN-38

Question 18

SN-38 in comparison to iriotecan?

Answer 18

SN-38 is the phase I metabolite product which is 100-1000 times more active than irinotecan.

Question 19

What is the phase II metabolism for SN-38/irinotecan?

Answer 19

The UDP-glucuronyltransferases (UGT) inactivates SN-38 to its SN-38G form

Question 20

What is UDP-glucuronyltransferases?

Answer 20

It is an enzyme of the glucuronidation pathway that transforms small lipophilic molecules such as steroids, bilirubin, hormones, and drugs into water-soluble, excretable metabolites by conjugating with glucuronic acid.

Question 21

What is the significance of the UGT1A1*28 polymorphism gene with respect to Irinotecan?

Answer 21

The variant has a longer repeat allele and lower hence resulting in lower corresponding UGT1A1 gene expression –> lower UGT –> higher SN-38 in blood

Question 22

What is the function of UGT1A1 which encodes for?

Answer 22

UGT

Question 23

What does UGT1A1*6 affect?

Answer 23

Decrease UGT activity

Question 24

What are the difference between UGT1A16 and UGT1A128?

Answer 24

UGT1A16 affects the activity of the UGT enzyme, but UGT1A128 affects the synthesis rate.