SS Lecture 50- Pharmacogenetics and Pharmacogenomics

Question 1

What are ADME genes?

Answer 1

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

Question 2

What are the two pharmacokinetic phases?

Answer 2

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

Question 3

Describe the genotype nomenclature for the P450 system.

Answer 3

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

Question 4

Describe the phenotype nomenclature for the P450 system.

Answer 4

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 5

Provide examples of genes involved in metabolism of common medications.

Answer 5

VKORC1
CYP2C19 (clopidogrel)
CYP2D6

Question 6

What genes are associated with metabolism of clopidogrel?

Answer 6

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 7

What genes are associated with the metabolism of codeine?

Answer 7

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 8

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

Answer 8

both CYP2D6 (UM mutations concern for toxicity) and CYP2C19

Question 9

What are the challenges for implementation of PGx in clinic?

Answer 9

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