Pharmacogenetics and Pharmacogenomics- Lecture 50

Question 1

Define pharmacogenetics.

Answer 1

study of drug responses in relation to genetic variation in specific candidate genes

Question 2

Define pharmacogenomics.

Answer 2

study of drug response in relation to genetic variation in the entire genome

Question 3

What are ADME genes?

Answer 3

genes that are involved in the absorption, distribution, metabolism, or excretion of a drug
influence pharmacokinetic aspects of drug metabolism

Question 4

What are the two pharmacokinetic phases?

Answer 4

phase 1 (oxidation, reduction, hydrolysis)
phase 2 (conjucation by a variety of biotransformation processes - acetylation, glucoronidation, sulfation, methylation)

Question 5

Describe the genotype nomenclature for the P450 system.

Answer 5

CYP2C19*2
(CYP) - superfamily
(2)- family
(C)- subfamily
(19)- isoform
(*2)- allele

Question 6

Describe the phenotype nomenclature for the P450 system.

Answer 6

Extensive (normal) metabolizers- 1* and 1*
Intermediate metabolizers- 1* and 2*
Poor metabolizers- 2* and 2*
(where 2* can be any loss of function mutation)

Question 7

Provide examples of genes involved in metabolism of common medications.

Answer 7

VKORC1
CYP2C19
CYP2D6

Question 8

What genes are associated with metabolism of clopidogrel?

Answer 8

inactive prodrug to active drug
CYP2C19 codes for enzymes aiding in processing of this in the liver (once the 15% is imported after the bottleneck)
loss of function mutations result in reduced efficiency and decreased likelihood to benefit from this treatment

Question 9

What genes are associated with the metabolism of codeine?

Answer 9

metabolized to morphine via enzymes coded for by the CYP2D6 gene
gain of function mutations (resulting in UM) –> concerns for toxicity
loss of function mutations (resulting in PM) –> concerns for reduced efficacy

Question 10

What genes are associated with the metabolism of TCAs and SSRIs?

Answer 10

both CYP2D6 (UM mutatants concern for toxicity) and CYP2C19

Question 11

What are the challenges for implementation of PGx in clinic?

Answer 11

genotype/phenotype relationships are not always clear cut
cost (reimbursement is sporadic)
need for fast results
post-testing counseling