Lecture 25 - Pharmacogenetics Flashcards
When examining inherited differences in drug responses, what two factors should be considered?
- drug efficacy
2. adverse drug reactions
Which of the following is not listed as important in recommended dosing?
A. Age B. Sex C. Body weight D. Presence of organ failure E. Trial and error F. Other Drugs
B. This is not a typical factor in dosing recommendations.
What is the drug mechanism of trastuzumab?
Targets the Her2 protein to treat metastatic breast cancer
What is the approved companion diagnostic test for Gleevac, which targets cell surface RTK c-kit?
c-kit immunohistochemical tests
Why are companion diagnostic tests important?
They help to determine a patient’s potential response to a particular drug.
Why is “reverse” genetic genotype-to-phenotype analysis performed?
To reveal how genomic variability translates to phenotypic variability (i.e. drug responses)
How many SNPs are present in humans (i.e. >1% of the population)?
10,000,000 SNPs
SNPs act by 3 general mechanisms - what are they?
- Coding non-synonymous (change coding sequence)
- Coding synonymous (no change in coding sequence; could change translational efficiency)
- Noncoding (promoter, intron, regulatory region)
Which of the 3 SNP mechanisms is responsible for altering the translational efficiency because the SNP generates a non-preferred codon?
Coding synonymous SNPs
If insertions/deletions are large enough, they can be considered:
CNVs (copy number variants)
Which of the 3 SNP mechanisms is responsible for a change in the coding sequence?
Coding non-synonymous SNPs
A ___________ is a variation in a number of a specific segment of DNA found in one or more populations.
CNV (copy number variant)
A duplication in the specific segment of the CYP2D6 gene is 10000 bp and associated with the “ultra-rapid metabolizer phenotype”. What genetic polymorphism is responsible?
CNV (copy number variant)
A given genetic polymorphism may affect drug action if it alters ___(list 4 targets)____ of a relevant gene target.
- expression level,
- subcellular localization,
- stability, or
- activity
Genome Wide Association Studies (GWAS) have shown that _______ account for the most genetic variation associated with complex human traits.
non-coding SNPs
Most genetic variants (including SNPs) that are likely to alter drug response are NOT contained where?
WithIN gene coding regions
Individual patient variation may exist in the following 5 factors that influence how much drug reaches the target organ:
- Absorption
- Distribution
- Excretion
- Metabolism
- Pharmacodynamics
Genetic polymorphisms in major, therapeutically relevant CYPs affect the ___________ of drugs.
A. Pharmacodynamics
B. Distribution
C. Substrate limitation
D. Pharmacokinetics
D. Pharmacokinetics is the affect on drug absorption and elimination.
What is the term for ‘altering drug concentrations at the site of action’ despite similar blood concentrations?
pharmacodynamics
CYP genetic polymorphisms affect pharmacokinetics of drugs, but they are also responsible for ___________ phenotypes.
different drug metabolizing phenotypes
Genetic polymorphisms in drug transporters can affect both __(a)__ and __(b)__ despite similar blood concentrations.
a) Pharmacokinetics (drug absorption and elimination)
b) Pharmacodynamics (concentration at the site of action)
Three general types of genes containing polymorphisms that affect drug action are:
- Common cytochrome P450s (CYPs)
- Transporters
- Receptors
The “multi-drug resistance-1” (MDR1) gene is which (of the 3 general types) genetic polymorphism?
Transporter
What might be responsible for variable responses of HIV-AIDS patients to HIV protease inhibitors?
Polymorphisms in the ABCB1 gene
__________ SNPs are the most common polymorphism found in ADBR2, the beta2-adrenergic receptor gene.
Coding non-synonymous SNPs
Trastuzumab is a treatment involving monoclonal antibodies directed against Her-2. Patients who are offered this treatment have what type of cancer? (Be specific!)
Breast cancer patients - with CNVs (gene amplification) of the Her-2 receptor.
Which alteration is NOT a result of genetic polymorphism influence on pharmacokinetics?
A. Alteration in drug metabolizing enzymes
B. Alteration in drug transporters
C. Alteration in drug target molecules
C. Drug target molecules are altered by pharmacodynamics of specific drugs.
Which alteration is NOT a result of genetic polymorphism influence on pharmacodynamics?
A. Alteration in drug metabolizing enzymes
B. Alteration in drug transporters
C. Alteration in drug target molecules
A. Drug-metabolizing enzymes are altered by pharmacokinetics of specific drugs.
Drug metabolizing enzymes are found mainly in the liver, but also in the intestine and kidney These enzymes are also involved int he metabolism of what type of molecules?
many endogenous circulating molecules (e.g. hormones, vitamins)
Which class of drug metabolizing enzymes in the liver catalyze oxidation/reduction and hydrolysis reactions?
Phase I enzymes
Which is NOT a function of Phase I metabolizing enzymes in the liver?
A. Catalyze oxidation B. Catalyze reduction C. Catalyze hydrolysis D. Catalyze conjugation E. Carried out by members of the cytochrome P450 (CYP) family of enzymes
D. Phase II enzymes catalyze conjugation reactions.
What class of drug metabolizing enzymes catalyze reactions of acetylation, glucuronidation, glutathionation, and sulfation?
Phase II enzymes
Metabolizing reactions have what two functions involving drug metabolism?
- transform into more water-soluble forms
2. aid in elimination
Some individuals, called “ultra-rapid metabolizers”, have greater ______ activity than average, usually due to two copies of the gene.
CYP2D6
Which is the major enzyme involved in the metabolism of the oral anticoagulant warfarin?
A. CYP2D6
B. CYP2C9
C. UGT1A1
B. Genetic variation in CYP2C9, as well as VKORC1, accounts for 30-40% of the clinical variation in warfarin response.
Which drug targets the Her2 protein to treat metastatic breast cancer?
A. Trastuzumab
B. Cetuximab
C. Gefitinib
D. Imatinib
A.
Which drug targets the EGFR/HER1 receptor in the treatment of colorectal cancer?
A. Trastuzumab
B. Cetuximab
C. Gefitinib
D. Imatinib
B.
Which drug targets the cell-surface tyrosine kinase receptor in treatment of gastrointestinal tumors?
A. Trastuzumab
B. Cetuximab
C. Gefitinib
D. Imatinib
D.
Which class of metabolizers are either homozygous for a gene variant associated with little or no enzyme activity or compound heterozygotes for two different variants?
A. Ultra-rapid metabolizers
B. Extensive metabolizers
C. Intermediate metabolizers
D. Poor metabolizers
D.
Which individuals typically have greater CYP2D6 activity than average?
A. Ultra-rapid metabolizers
B. Extensive metabolizers
C. Intermediate metabolizers
D. Poor metabolizers
A.
Individuals who are homozygous for the ____ allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment.
A. CYP2D6
B. CYP2C9
C. UGT1A1*28
C.
___________ specific polymorphisms are present in all ethnic groups with different frequencies among those groups.
Cosmopolitan (racial)
Note: these are older than ethnically-specific polymorphisms.
