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Questions and Answers
What is the expected activity level of a TMPT homozygote with a genotype of (v/v)?
What is the expected activity level of a TMPT homozygote with a genotype of (v/v)?
What percentage reduction in dose can be achieved by dosing based on TPMT genotype?
What percentage reduction in dose can be achieved by dosing based on TPMT genotype?
Which CFTR mutation is the most common in Ireland?
Which CFTR mutation is the most common in Ireland?
Which medication is known to respond well to class III & IV mutations in cystic fibrosis?
Which medication is known to respond well to class III & IV mutations in cystic fibrosis?
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Which statement regarding warfarin is accurate?
Which statement regarding warfarin is accurate?
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What is the primary concern when increasing the dose of a medication with a narrow therapeutic range?
What is the primary concern when increasing the dose of a medication with a narrow therapeutic range?
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What effect do VKORC1 polymorphisms generally have on warfarin dosing?
What effect do VKORC1 polymorphisms generally have on warfarin dosing?
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How is warfarin dosing monitored clinically?
How is warfarin dosing monitored clinically?
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What is the result of a loss-of-function CYP2C9 polymorphism related to warfarin?
What is the result of a loss-of-function CYP2C9 polymorphism related to warfarin?
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Which factors can further complicate the dosing of medications with a narrow therapeutic range?
Which factors can further complicate the dosing of medications with a narrow therapeutic range?
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What is the main function of phase I metabolism in drug processing?
What is the main function of phase I metabolism in drug processing?
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Which of the following enzymes is primarily involved in the metabolism of more than 75% of drugs?
Which of the following enzymes is primarily involved in the metabolism of more than 75% of drugs?
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What type of drugs can interfere with the conversion of tamoxifen?
What type of drugs can interfere with the conversion of tamoxifen?
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What is the primary clinical use of azathioprine?
What is the primary clinical use of azathioprine?
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What is the consequence of TPMT deficiency in patients treated with azathioprine?
What is the consequence of TPMT deficiency in patients treated with azathioprine?
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Which metabolite of azathioprine is responsible for its major activity?
Which metabolite of azathioprine is responsible for its major activity?
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What is the primary action of mercaptopurine?
What is the primary action of mercaptopurine?
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What is the main consequence of myelosuppression caused by azathioprine?
What is the main consequence of myelosuppression caused by azathioprine?
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What is the primary role of CYP2D6 in drug metabolism?
What is the primary role of CYP2D6 in drug metabolism?
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Which factor is NOT considered an environmental influence on drug response?
Which factor is NOT considered an environmental influence on drug response?
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What does the term 'off target' genes refer to in pharmacogenetics?
What does the term 'off target' genes refer to in pharmacogenetics?
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What can be a consequence of being a poor metabolizer for CYP2D6?
What can be a consequence of being a poor metabolizer for CYP2D6?
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Which scenario illustrates a polygenic effect in pharmacogenomics?
Which scenario illustrates a polygenic effect in pharmacogenomics?
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What is a potential risk for ultrafast metabolizers of pro-drugs like codeine?
What is a potential risk for ultrafast metabolizers of pro-drugs like codeine?
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What is the primary challenge in predicting drug response?
What is the primary challenge in predicting drug response?
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Which statement is true regarding the role of genetic variation in drug response?
Which statement is true regarding the role of genetic variation in drug response?
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Which polymorphism primarily explains the variability in warfarin dose requirements?
Which polymorphism primarily explains the variability in warfarin dose requirements?
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What percentage of dose variability does CYP2C9 genotype explain for warfarin dosage?
What percentage of dose variability does CYP2C9 genotype explain for warfarin dosage?
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What severe adverse reaction is characterized by the separation of epidermis from dermis?
What severe adverse reaction is characterized by the separation of epidermis from dermis?
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Which genetic variant is linked with an increased risk for Stevens Johnson Syndrome when using carbamazepine?
Which genetic variant is linked with an increased risk for Stevens Johnson Syndrome when using carbamazepine?
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What is the incidence rate of Stevens Johnson Syndrome in the general population?
What is the incidence rate of Stevens Johnson Syndrome in the general population?
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Since what year has the FDA recommended genetic testing for warfarin use?
Since what year has the FDA recommended genetic testing for warfarin use?
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Which drug has a known strong association with HLA-B*1502 in relation to Stevens Johnson Syndrome?
Which drug has a known strong association with HLA-B*1502 in relation to Stevens Johnson Syndrome?
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What does VKORC1 polymorphism influence in patients using warfarin?
What does VKORC1 polymorphism influence in patients using warfarin?
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Which genotype pairing is associated with high enzyme activity?
Which genotype pairing is associated with high enzyme activity?
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What type of mutations in the CFTR genes can be treated effectively with ivacaftor?
What type of mutations in the CFTR genes can be treated effectively with ivacaftor?
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Which transport mechanism is primarily involved in the metabolism of drugs like tacrolimus?
Which transport mechanism is primarily involved in the metabolism of drugs like tacrolimus?
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What is the outcome of dosing medications based on TPMT genotype?
What is the outcome of dosing medications based on TPMT genotype?
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Which of the following statements is true regarding the most common CFTR mutation in Ireland?
Which of the following statements is true regarding the most common CFTR mutation in Ireland?
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What may be a consequence of increased warfarin dosage due to its narrow therapeutic range?
What may be a consequence of increased warfarin dosage due to its narrow therapeutic range?
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Which factor is likely to affect warfarin sensitivity and dosing requirements due to polymorphisms?
Which factor is likely to affect warfarin sensitivity and dosing requirements due to polymorphisms?
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What is the main role of CYP2C9 in relation to warfarin?
What is the main role of CYP2C9 in relation to warfarin?
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How do VKORC1 polymorphisms typically affect warfarin dosing in patients?
How do VKORC1 polymorphisms typically affect warfarin dosing in patients?
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What complication is associated with a loss-of-function CYP2C9 polymorphism?
What complication is associated with a loss-of-function CYP2C9 polymorphism?
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What is the main consequence of azathioprine's metabolism through thiopurine methyl transferase?
What is the main consequence of azathioprine's metabolism through thiopurine methyl transferase?
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Which statement describes the role of UGT enzymes in drug metabolism?
Which statement describes the role of UGT enzymes in drug metabolism?
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What effect does CYP2D6 activity have on tamoxifen treatment?
What effect does CYP2D6 activity have on tamoxifen treatment?
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Which of the following statements about mercaptopurine is true?
Which of the following statements about mercaptopurine is true?
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What is a characteristic of polymorphisms in the gene encoding TPMT?
What is a characteristic of polymorphisms in the gene encoding TPMT?
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What is the primary metabolic fate of azathioprine when metabolized by xanthine oxidase?
What is the primary metabolic fate of azathioprine when metabolized by xanthine oxidase?
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What is a potential outcome for individuals who are poor metabolizers of CYP2D6 when taking codeine?
What is a potential outcome for individuals who are poor metabolizers of CYP2D6 when taking codeine?
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How does poor metabolizer status for CYP2D6 influence drug therapy?
How does poor metabolizer status for CYP2D6 influence drug therapy?
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Which of the following statements most accurately describes the role of CYP2D6 in drug metabolism?
Which of the following statements most accurately describes the role of CYP2D6 in drug metabolism?
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Which statement accurately reflects the role of phase I metabolism in drug processing?
Which statement accurately reflects the role of phase I metabolism in drug processing?
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In terms of pharmacogenomics, how can responses to drugs be classified?
In terms of pharmacogenomics, how can responses to drugs be classified?
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What is a common misconception regarding the clinical relevance of genetic variation in drug metabolism?
What is a common misconception regarding the clinical relevance of genetic variation in drug metabolism?
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What distinguishes 'off-target' genes in pharmacogenetics?
What distinguishes 'off-target' genes in pharmacogenetics?
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What challenge exists when determining the correct drug and dose for a patient?
What challenge exists when determining the correct drug and dose for a patient?
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Why might ultrafast metabolizers of codeine experience adverse effects?
Why might ultrafast metabolizers of codeine experience adverse effects?
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Which aspect of genetic variation is particularly significant in pharmacogenetics?
Which aspect of genetic variation is particularly significant in pharmacogenetics?
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What percentage of warfarin dose variability can VKORC1 genotype explain?
What percentage of warfarin dose variability can VKORC1 genotype explain?
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Which of the following best describes the relationship between CYP2C9 and warfarin dosage?
Which of the following best describes the relationship between CYP2C9 and warfarin dosage?
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What is the incidence rate of Stevens Johnson Syndrome (SJS) in the general population?
What is the incidence rate of Stevens Johnson Syndrome (SJS) in the general population?
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What is a major cause of Stevens Johnson Syndrome?
What is a major cause of Stevens Johnson Syndrome?
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Which statement is true regarding the FDA's recommendations for HLA-B*1502 testing?
Which statement is true regarding the FDA's recommendations for HLA-B*1502 testing?
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What is the estimated frequency of HLA-B*1502 globally?
What is the estimated frequency of HLA-B*1502 globally?
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Which characteristic of VKORC1 polymorphisms influences warfarin dosing?
Which characteristic of VKORC1 polymorphisms influences warfarin dosing?
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What was the significant finding regarding the association of HLA-B*1502 with carbamazepine use?
What was the significant finding regarding the association of HLA-B*1502 with carbamazepine use?
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Study Notes
Pharmacogenetics
- Pharmacogenetics is the study of how genetic variation affects drug response.
- It is a powerful tool for predicting drug response.
- Genetic variations can affect both pharmacokinetics (how the body processes a drug) and pharmacodynamics (how a drug affects the body).
- It focuses on the influence of genetic variations on drug metabolism, drug targets, and off-target genes.
Environmental Factors Affecting Drug Response
- Environmental factors such as age, diet, organ function, underlying disease, and concomitant therapy can influence drug response.
Genetic Variation & Drug Metabolism
- Cytochrome P450 (CYP) enzymes play a crucial role in drug metabolism.
- Genetic variations in CYP genes can lead to differences in drug metabolism and therefore, drug efficacy and toxicity.
- CYP2D6 is an important enzyme involved in the metabolism of codeine, tamoxifen, and other drugs.
- Poor metabolizers of codeine will experience less therapeutic effect with standard dosing.
- Ultrafast metabolizers of codeine have a higher risk of drug intoxication.
- Tamoxifen is a prodrug that requires CYP2D6 for conversion to its active form (endoxifen).
Phase I and Phase II Metabolism
- Phase I metabolism introduces functional groups like -OH, -NH2, and -COOH into drug molecules, preparing them for phase II metabolism.
- Phase II metabolism involves conjugation of drug molecules with hydrophilic groups, increasing their water solubility and facilitating excretion.
Candidate Gene Example 1: Mercaptopurine
- Mercaptopurine inhibits purine nucleotide synthesis and is used to treat conditions like leukemia, inflammatory bowel disease, and organ transplants.
- Toxicity is a concern as mercaptopurine can cause myelosuppression.
- Thiopurine methyltransferase (TPMT) is a key enzyme in mercaptopurine metabolism.
- TPMT deficiency can lead to accumulation of toxic mercaptopurine metabolites, resulting in myelosuppression.
- Genetic testing for TPMT genotype is recommended to adjust mercaptopurine dosing, thereby reducing the incidence of toxicity.
Drug Targets and Genetic Variation
- Genetic variations in drug targets can affect drug efficacy and safety.
- Calcineurin, a protein target for immunosuppressants like tacrolimus and ciclosporin, can be affected by genetic variations.
- Drug transport proteins, such as ABC1/P-glycoprotein (P-gp), can also be affected by genetic variations.
- Genetic variations in P-gp can influence drug absorption and elimination.
Cystic Fibrosis and CFTR Gene Mutations
- Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- DeltaF508 is the most common CFTR mutation, followed by G551D.
- Kalydeco/Ivacaftor is a drug that can effectively treat individuals with specific CFTR mutations, primarily Class III and IV.
Warfarin and Genetic Variations
- Warfarin is an anticoagulant drug with a narrow therapeutic index.
- VKORC1 (vitamin K epoxide reductase complex 1) and CYP2C9 are important genes involved in warfarin metabolism and response.
- Genetic variation in VKORC1 affects warfarin requirements, with certain polymorphisms associated with lower dose requirements.
- Genetic variation in CYP2C9 also influences warfarin requirements, with loss-of-function variations leading to higher active drug concentrations.
Stevens Johnson Syndrome (SJS)
- SJS is a severe adverse drug reaction characterized by separation of the epidermis from the dermis.
- It is often triggered by pharmaceuticals.
- HLA-B*1502 is a specific HLA allele strongly associated with carbamazepine-induced SJS in Asian populations.
- Genetic testing for HLA-B*1502 is recommended for individuals of Asian descent prior to carbamazepine exposure.
- Further research is ongoing to identify additional genetic factors influencing SJS susceptibility.
Pharmacogenetics
- Pharmacogenetics is the study of how genetic variations affect drug response.
- Some people may respond differently to a specific drug dose due to genetic differences.
Clinical Relevance of Genetic Variation in Drug Metabolism
- CYP2D6 is a key enzyme involved in drug metabolism and shows significant genetic variation.
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Codeine is metabolized by CYP2D6 to morphine.
- Poor metabolizers of CYP2D6 experience reduced therapeutic effects from standard codeine doses.
- Ultrafast metabolizers experience increased morphine levels, potentially leading to intoxication.
-
Tamoxifen is a breast cancer drug that is converted to its active form, endoxifen, by CYP2D6.
- Different CYP2D6 alleles lead to variations in tamoxifen metabolism, affecting drug effectiveness.
Mercaptopurine and Azathioprine
- Mercaptopurine and azathioprine are drugs used to treat various conditions, including leukemia, inflammatory bowel disease, and organ transplants.
- These drugs inhibit purine nucleotide synthesis, disrupting DNA replication.
- A key enzyme involved in their metabolism is thiopurine methyltransferase (TPMT)
- TPMT deficiency leads to increased levels of 6-mercaptopurine, resulting in toxicity.
- Genetic testing for TPMT genotypes is recommended to guide drug dosing and minimize toxicity.
Warfarin
- Warfarin is an anticoagulant used to prevent blood clots.
- It has a narrow therapeutic range, making accurate dosing crucial.
-
VKORC1 and CYP2C9 polymorphisms influence warfarin metabolism and response.
- VKORC1 variations often result in greater response to warfarin, requiring lower doses.
- CYP2C9 variations can lead to higher active drug levels, potentially increasing toxicity.
- Genetic testing for VKORC1 and CYP2C9 is recommended to guide warfarin dosing.
Cystic Fibrosis
- Cystic fibrosis is caused by mutations in the CFTR gene.
- DeltaF508 is the most common CFTR mutation, followed by G551D.
- Kalydeco/ivacaftor is a drug that effectively treats some CFTR mutations, particularly class III and IV mutations.
Stevens-Johnson Syndrome (SJS)
- SJS is a severe adverse drug reaction characterized by skin separation.
- HLA-B*1502 is strongly associated with carbamazepine-induced SJS in individuals of Asian descent.
- Genetic testing for HLA-B*1502 is recommended in Asian populations before carbamazepine therapy to reduce SJS risk.
- Additional genetic testing may be required to identify other SJS risk factors in other populations.
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Description
This quiz explores the fundamentals of pharmacogenetics, focusing on how genetic variations impact drug metabolism and effectiveness. It also examines the role of environmental factors and specific enzymes like CYP2D6 in drug response. Test your knowledge on the interplay between genetics and pharmacology.
