Pharm 411-Pharmacogenomics

Question 1

Define Pharmacogenomics

Answer 1

The study of how the response to drugs is influences by which gene sequences are present in a pt.

Question 2

Define polymorphisms

Answer 2

Genetic Variation(Variation in DNA sequence)
Must seen >1%

Question 3

What is the goal of pharmacogenomics?

Answer 3

-To understand how the genetic composition of an indiv will alter the response to a drug for that pt can be chosen at the start

Question 4

what can alter a change of the efficacy and/or toxicity of a drug?

Answer 4

Change in PK or PD.

-Influence drug dosing or selection of alternative therapies.

Question 5

Define Genotype

Answer 5

-The genetic makeup of an organism

Question 6

What is the most common type of genotype called?

Answer 6

-Wild

Question 7

Define phenotype

Answer 7

-The visible properties of an organism that are produced by the interaction of the genotype and the environment
=>Basically appearance.

Question 8

Define allele

Answer 8

The version/type of a gene

Two alleles make up an individual’s genotype for that gene

Question 9

What is Haplotype

Answer 9

A set of polymorphisms that are inherited together from a single parent
(a set of SNPs on the same chromosome)
-Refer to both a combination of different alleles,

Question 10

What is Haplogroup?

Answer 10

Sets of haplotypes that come from a common ancestor; have a branch point of a single SNP at some point
( GROUPS of similar halotypes)k

Question 11

-SNP, coding regions consists of?

Answer 11

• Coding polymorphisms
• Synonymous SNP: nucleotide change without a change in amino acid (silent)
• Nonsynonymous SNP: nucleotide change with a change in amino acid (missense)
• Premature stop codon SNP: nucleotide change that introduces an early stop codon (nonsense)

Question 12

SNP, Non coding polymorphisms consist of?

Answer 12

• Intergenic DNA such as in promoters, introns, or other regulatory regions
• May alter transcription factor binding, mRNA transcript stability, or RNA splicing

Question 13

How many parts are there in SNA? what are they?

Answer 13

1)Gene name (normally italicized)
2)Nucleotide position
3)Actual polymorphism notation
First letter is the normal nucleotide
Second letter is the mutated nucleotide

Question 14

What is pharmacokinetics and what is its affect?

Answer 14

-ADME
-Pharmacokinetics determines how much drug is available at the site of action
-Any mutation that is involved in ADME will change the pharmacokinetics of a drug
-Some examples of polymorphisms that impact PK are:
Polymorphisms in cytochrome P450s

Question 15

Define Cytochrome P450s

Answer 15

Cytochrome P450s are a diverse group of metabolic enzymes which have a high concentration of polymorphisms

Question 16

CYP 450, polymorphism usually result in?

Answer 16

-Reduced function or lack of function

Question 17

How many phenotypes are observed in CYP P450?

Answer 17

PM, IM, EM, UM

Question 18

What is Irinotecan?

in terms of its indication, MOA, Gene/allele of interest, popuation concern, FDA requires testing?

Answer 18

-Indication: Oncology
-Mechanism of action: Topoisomerase inhibitor
-Gene/allele of interest: UGT1A128
-Functional effect(s): UGT1A128 has decreased transcription
>Decreased expression leads to decreased metabolism of irinotecan
-Population prevalence of UGT1A1*28
-African: 43%

Question 19

Is Irinotecan is a prodrug or active drug?

Answer 19

Pro drug, becomes SN-38. UGT metablolizes SN-38 , not pro drug

Question 20

What is Thiopurine Methyltransferase (TPMT)

What is the prodrug of 6-mercaptopurine

Answer 20

• Phase II metabolic enzyme

- Metolism fro all thipurines: Azathioprine is a prodrug of 6-mercaptopurine

Question 21

What is OATPs responsible for?

Answer 21

OATPs are responsible for transporting manydrugs into the liver for elimination

Question 22

What is pharmacodynamics?

Answer 22

• Action
• MOA
• the effect of the drug on the body and how well it interacts with its target (efficacy)

Question 23

What is HLA-B?

Answer 23

-HLA-B is a gene located in the major histocompatibility complex which produces a protein which can recognize foreign substances and activates the immune system to destroy them.

Question 24

Abacavir (Ziagen), indication, MOA, gene of interest, population concern
Genetic test required by FDA?
-HLA-B*5702

Answer 24

Indication:
-HIV infection
Mechanism of action: NRTIs
Gene/allele of interest:
-HLA-B*5701 
-Required test by FDA

Question 25

Carbamazepine (Tegretol), | -HLA-B*1502

Answer 25

``` -Indication: Seizure disorders, in particular epilepsy -Mechanism of action: Blocks voltage-gated sodium channel -Gene/allele of interest: HLA-B*1502 -Required test by FDA ```

Question 26

Trastuzumab (Herceptin) | -HER2

Answer 26

-Indication: Metastatic breast cancer -Mechanism of Action: Antibody binds to the extracellular domain of the HER2 receptor and prevents its use for signaling -Gene/allele of interest: HER2 overexpression in breast cancer cells

Question 27

Clopidogrel (Plavix) | -CYP219 *2 or*3

Answer 27

-Indication: Antiplatelet agent used for reduction of atherosclerotic events (e.g. myocardial infarction, stroke, and vascular death) -Mechanism of action: Inhibitor of platelet activation/aggregation by irreversible inhibition of ADP-P2Y receptors -Metabolized to its active form by CYP2C19 -Gene/allele of interest: CYP2C19 Population concern: Asians: 25% -Recommended testing prior to beginning treatment.

Question 28

Azathioprine (Azasan, Imuran) | -TPMT

Answer 28

-Indication: Rheumatoid arthritis, renal transplantation -Mechanism of action: immune suppressant Prodrug of 6-mercaptopurine; incorporated into DNA Inhibits de novo purine synthesis -Gene/allele of interest: TPMT

Question 29

Warfarin (Coumadin) - CYP2C9 - VKORC1

Answer 29

-Indication: Anticoagulant.Thrombotic events (irregular heartbeat, prosthetic heart valves, and heart attack) -Mechanism of action: Prevents blood clotting by blocking the utilization of vitamin K during the synthesis of clotting factors. Without vitamin K the body cannot produce clotting factors and blood will not clot -Gene/allele of interest: Both the target of warfarin (VKORC1) and the metabolic enzymes (CYP2C9) are points of human polymorphisms -Population: VKORC1 Asains, 92%, African-American 44% , Causcation 37%

Question 30

Irinotecan | -UGT1A1*28

Answer 30

``` -Indication: Oncology -Mechanism of action: Topoisomerase inhibitor -Gene/allele of interest UGT1A1*28 -Functional effect(s) UGT1A1*28 has decreased transcription Decreased expression leads to decreased metabolism of irinotecan -Population prevalence of UGT1A1*28 African: 43% Caucasian: 39% ```

Question 31

OATP1B1 - OATP1B1*5 - OATP1B1*15

Answer 31

-an influx transporter expressed in human hepatocytes -Mediates the uptake of compounds from the portal blood lowering plasma concentration -A SNP in OATP1B1 decreases the activity (thus increasing the plasma concentration of substrates) -OATP1B1*5 (OATP1B1 521T>C) -OATP1B1*15 (OATP1B1 388A>G, 521T>C) Combined these two alleles are found in: 15-20% of Caucasians 10-15% of Asians

Question 32

What is synonymous SNP?

Answer 32

-A nucleotide change without a change in amino acid | SILENT

Question 33

What is Coding polymorphisms consists of?

Answer 33

Synonymous-silent nonsynomous-missense premature stop codon-nonsense

Question 34

What is nonsynonymous SNP?

Answer 34

nucletodei change WITH a change in amino acid | Missense

Question 35

What is premature stop codon SNP?

Answer 35

-nucleotide change that introduces an early STOP condon | nonsense

Question 36

What is Non-coding polymorphism? Where is it found?

Answer 36

- Found in the intergenic DNA such as promotres, introns, or other regulatory regions - ALTER transcription factor binding , mRA transcript stability, or RNA splicing

Question 37

What are the other types of polymorphism?

Answer 37

- Insertions and deletions | - Extra gene copies

Question 38

Pharmacokinetics determines?

Answer 38

Ho much drug is avai. | At the site of action

Question 39

What are some examples of pharmacokinetics?

Answer 39

P450s, UGT T1A1 TPMT OATP1B1

Question 40

Polymorphism usually result in induced or reduced function?

Answer 40

- Reduced function or lack of function | - Lead to change in amount of drug that is metabolized

Question 41

What differentiates between a mutation and a polymorphism?

Answer 41

-Frequency of mutation

Question 42

Range Haplotype, Haplygroup, SNP in order from smallest to biggest

Answer 42

SNP < Haplotype < Haplogroup