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PHAR 411-Pharmacogenomics > Pharm 411-Pharmacogenomics > Flashcards

Pharm 411-Pharmacogenomics Flashcards

1
Q

Define Pharmacogenomics

A

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

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2
Q

Define polymorphisms

A 
Genetic Variation(Variation in DNA sequence)
Must seen >1%
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3
Q

What is the goal of pharmacogenomics?

A

-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

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4
Q

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

A

Change in PK or PD.

-Influence drug dosing or selection of alternative therapies.

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5
Q

Define Genotype

A

-The genetic makeup of an organism

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6
Q

What is the most common type of genotype called?

A

-Wild

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7
Q

Define phenotype

A

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

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8
Q

Define allele

A

The version/type of a gene

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

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9
Q

What is Haplotype

A

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,

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10
Q

What is Haplogroup?

A

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

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11
Q

-SNP, coding regions consists of?

A
  • 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)
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12
Q

SNP, Non coding polymorphisms consist of?

A
  • Intergenic DNA such as in promoters, introns, or other regulatory regions
  • May alter transcription factor binding, mRNA transcript stability, or RNA splicing
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13
Q

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

A

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

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14
Q

What is pharmacokinetics and what is its affect?

A

-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

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15
Q

Define Cytochrome P450s

A

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

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16
Q

CYP 450, polymorphism usually result in?

A

-Reduced function or lack of function

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17
Q

How many phenotypes are observed in CYP P450?

A

PM, IM, EM, UM

18
Q

What is Irinotecan?

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

A

-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%

19
Q

Is Irinotecan is a prodrug or active drug?

A

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

20
Q

What is Thiopurine Methyltransferase (TPMT)

What is the prodrug of 6-mercaptopurine

A
  • Phase II metabolic enzyme

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

21
Q

What is OATPs responsible for?

A

OATPs are responsible for transporting manydrugs into the liver for elimination

22
Q

What is pharmacodynamics?

A
  • Action
  • MOA
  • the effect of the drug on the body and how well it interacts with its target (efficacy)
23
Q

What is HLA-B?

A

-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.

24
Q

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

A 
Indication:
-HIV infection
Mechanism of action: NRTIs
Gene/allele of interest:
-HLA-B*5701 
-Required test by FDA
25
Q

Carbamazepine (Tegretol),

-HLA-B*1502

A 
-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
26
Q

Trastuzumab (Herceptin)

-HER2

A

-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

27
Q

Clopidogrel (Plavix)

-CYP219 2 or3

A

-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.

28
Q

Azathioprine (Azasan, Imuran)

-TPMT

A

-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

29
Q

Warfarin (Coumadin)

  • CYP2C9
  • VKORC1
A

-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%

30
Q

Irinotecan

-UGT1A1*28

A 
-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%
31
Q

OATP1B1

  • OATP1B1*5
  • OATP1B1*15
A

-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)
-OATP1B15 (OATP1B1 521T>C)
-OATP1B115 (OATP1B1 388A>G, 521T>C)
Combined these two alleles are found in:
15-20% of Caucasians
10-15% of Asians

32
Q

What is synonymous SNP?

A

-A nucleotide change without a change in amino acid

SILENT

33
Q

What is Coding polymorphisms consists of?

A

Synonymous-silent
nonsynomous-missense
premature stop codon-nonsense

34
Q

What is nonsynonymous SNP?

A

nucletodei change WITH a change in amino acid

Missense

35
Q

What is premature stop codon SNP?

A

-nucleotide change that introduces an early STOP condon

nonsense

36
Q

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

A
  • Found in the intergenic DNA such as promotres, introns, or other regulatory regions
  • ALTER transcription factor binding , mRA transcript stability, or RNA splicing
37
Q

What are the other types of polymorphism?

A
  • Insertions and deletions

- Extra gene copies

38
Q

Pharmacokinetics determines?

A

Ho much drug is avai.

At the site of action

39
Q

What are some examples of pharmacokinetics?

A

P450s,
UGT T1A1
TPMT
OATP1B1

40
Q

Polymorphism usually result in induced or reduced function?

A
  • Reduced function or lack of function

- Lead to change in amount of drug that is metabolized

41
Q

What differentiates between a mutation and a polymorphism?

A

-Frequency of mutation

42
Q

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

A

SNP < Haplotype < Haplogroup

PHAR 411-Pharmacogenomics (2 decks)

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