Podcast
Questions and Answers
Which of the following best describes the focus of pharmacogenetics?
Which of the following best describes the focus of pharmacogenetics?
- The broad study of how genes affect a person's response to drugs, including variations in multiple genes.
- The examination of a single gene-drug interaction and its impact on drug response. (correct)
- The study of how the body processes drugs, including absorption, distribution, metabolism, and excretion.
- The study of the effect of drugs on the body, including the mechanism of action and therapeutic effects.
A patient with decreased CYP2C19 enzyme activity is prescribed clopidogrel. How might this genetic variation affect the drug's effectiveness?
A patient with decreased CYP2C19 enzyme activity is prescribed clopidogrel. How might this genetic variation affect the drug's effectiveness?
- No significant impact, as clopidogrel is directly active and does not require metabolic activation.
- Increased conversion of clopidogrel to its active form, leading to enhanced therapeutic effect.
- Increased risk of side effects due to higher concentrations of the inactive prodrug.
- Decreased conversion of clopidogrel to its active form, increasing the risk of blood clots. (correct)
A patient is identified as a CYP2D6 ultra-rapid metabolizer. If prescribed codeine for pain relief, what is the most likely clinical consequence?
A patient is identified as a CYP2D6 ultra-rapid metabolizer. If prescribed codeine for pain relief, what is the most likely clinical consequence?
- Prolonged pain relief due to slower elimination of codeine.
- Increased risk of adverse effects, such as respiratory depression, due to increased morphine production. (correct)
- Reduced pain relief due to decreased conversion of codeine to morphine.
- No change in pain relief or side effects, as CYP2D6 does not affect codeine metabolism.
Which of the following is an example of a synonymous genetic polymorphism?
Which of the following is an example of a synonymous genetic polymorphism?
A patient is taking bupropion for depression and requires pain relief. If tramadol is considered, what pharmacogenetic consideration is most important?
A patient is taking bupropion for depression and requires pain relief. If tramadol is considered, what pharmacogenetic consideration is most important?
What is the likely consequence of an increased function allele on the AUC of a drug?
What is the likely consequence of an increased function allele on the AUC of a drug?
A patient is prescribed warfarin. Which CYP2C9 genotype would likely necessitate a lower starting dose?
A patient is prescribed warfarin. Which CYP2C9 genotype would likely necessitate a lower starting dose?
In the context of pharmacogenomics, what does 'phenoconversion' describe?
In the context of pharmacogenomics, what does 'phenoconversion' describe?
A drug is metabolized by an enzyme that exhibits genetic polymorphism. If a patient has a genetic variation that results in increased enzyme activity, how might this impact drug dosing?
A drug is metabolized by an enzyme that exhibits genetic polymorphism. If a patient has a genetic variation that results in increased enzyme activity, how might this impact drug dosing?
A patient is prescribed a drug that is a substrate of CYP3A4/5. Considering genetic variations in CYP3A5, which population is more likely to be an 'expresser' phenotype (NM or IM)?
A patient is prescribed a drug that is a substrate of CYP3A4/5. Considering genetic variations in CYP3A5, which population is more likely to be an 'expresser' phenotype (NM or IM)?
A patient is identified as a poor metabolizer for DPYD. What is the primary clinical consideration when prescribing fluoropyrimidines (e.g., 5-FU)?
A patient is identified as a poor metabolizer for DPYD. What is the primary clinical consideration when prescribing fluoropyrimidines (e.g., 5-FU)?
A patient is prescribed irinotecan. Which genetic variation in UGT1A1 is associated with increased risk of toxicity from irinotecan?
A patient is prescribed irinotecan. Which genetic variation in UGT1A1 is associated with increased risk of toxicity from irinotecan?
A patient is starting isoniazid for tuberculosis treatment. Which NAT2 phenotype is most likely to experience adverse effects related to slower drug metabolism?
A patient is starting isoniazid for tuberculosis treatment. Which NAT2 phenotype is most likely to experience adverse effects related to slower drug metabolism?
Why might genetic testing for TPMT be important before starting a patient on azathioprine?
Why might genetic testing for TPMT be important before starting a patient on azathioprine?
For a patient taking a drug A, which is an active drug metabolized by CYP2D6 into an inactive metabolite. A CYP2D6 inhibitor, drug B, is added. What is the expected effect on parent drug A?
For a patient taking a drug A, which is an active drug metabolized by CYP2D6 into an inactive metabolite. A CYP2D6 inhibitor, drug B, is added. What is the expected effect on parent drug A?
A patient is taking clopidogrel. Which CYP2C19 phenotype would be most concerning and potentially warrant an alternative antiplatelet therapy?
A patient is taking clopidogrel. Which CYP2C19 phenotype would be most concerning and potentially warrant an alternative antiplatelet therapy?
A patient is taking drug X which shows elevated plasma concentrations after fluvoxamine is added. Drug X is exclusively metabolized by CYP2C19. What is the most likely explanation for this observation?
A patient is taking drug X which shows elevated plasma concentrations after fluvoxamine is added. Drug X is exclusively metabolized by CYP2C19. What is the most likely explanation for this observation?
A patient is found to have a CYP2A6*4/*4 genotype. What effect will this likely have on nicotine metabolism?
A patient is found to have a CYP2A6*4/*4 genotype. What effect will this likely have on nicotine metabolism?
A patient is taking Efavirenz. If the patient is found to be a CYP2B6 ultra-rapid metabolizer, what change in the standard dose would be ideal?
A patient is taking Efavirenz. If the patient is found to be a CYP2B6 ultra-rapid metabolizer, what change in the standard dose would be ideal?
A patient is prescribed the CYP2C8 substrate rosiglitazone. If this patient is also taking rifampin, what is the expected interaction?
A patient is prescribed the CYP2C8 substrate rosiglitazone. If this patient is also taking rifampin, what is the expected interaction?
A patient with a known CYP2C9 polymorphism is prescribed ibuprofen for pain. What is the most relevant consideration regarding this drug-gene interaction?
A patient with a known CYP2C9 polymorphism is prescribed ibuprofen for pain. What is the most relevant consideration regarding this drug-gene interaction?
A patient taking warfarin also starts amiodarone. How would you describe this interaction, and how will it change warfarin concentrations?
A patient taking warfarin also starts amiodarone. How would you describe this interaction, and how will it change warfarin concentrations?
In determining if drug dosing changes should be made, what drug concentration would be ideal?
In determining if drug dosing changes should be made, what drug concentration would be ideal?
Genetic polymorphisms can have different consequences. Which of the following is most likely to cause a premature stop codon?
Genetic polymorphisms can have different consequences. Which of the following is most likely to cause a premature stop codon?
For a prodrug, what is the effect of decreased enzyme activity?
For a prodrug, what is the effect of decreased enzyme activity?
What is one of the key questions to consider regarding gene-drug relationships?
What is one of the key questions to consider regarding gene-drug relationships?
What phenotypes for drug metabolizing enzymes are standardized, according to the text?
What phenotypes for drug metabolizing enzymes are standardized, according to the text?
When it comes to therapeutic window, what exists above the line of toxicity?
When it comes to therapeutic window, what exists above the line of toxicity?
In comparing pharmacogenomics and pharmacogenetics, which statement is most accurate?
In comparing pharmacogenomics and pharmacogenetics, which statement is most accurate?
Which CYP2C19 allele results in no function?
Which CYP2C19 allele results in no function?
Which of the following is NOT a substrate of CYP2D6?
Which of the following is NOT a substrate of CYP2D6?
Which of the following CYP3A4/5 alleles is a no function allele?
Which of the following CYP3A4/5 alleles is a no function allele?
Which of the following correctly lists the CYP2D6 phenotype groups in the figure below going in order from 1 to 4?
Which of the following correctly lists the CYP2D6 phenotype groups in the figure below going in order from 1 to 4?
A patient with chronic pain who may be treated with codeine is genotyped for CYP2D6. The result indicates the patient's diplotype is CYP2D6*1/*4. What is this patient's activity score?
A patient with chronic pain who may be treated with codeine is genotyped for CYP2D6. The result indicates the patient's diplotype is CYP2D6*1/*4. What is this patient's activity score?
Which of the following enzyme and phase I/II metabolism pairs are correct?
Which of the following enzyme and phase I/II metabolism pairs are correct?
KP is a 43-year-old female with a PMH significant for type II diabetes mellitus, hypertension, major depressive disorder, chronic pain, and seasonal allergies presents to clinic after undergoing pharmacogenomic testing. Which medication(s) is KP currently taking that inhibit CYP2D6? Current Medications: Acetaminophen 650 mg tablet by mouth every 6 hours as needed Bupropion 24-hour extended-release (Wellbutrin XL) 300 mg tablet by mouth once daily Loratadine 10 mg tablet by mouth once daily Metformin 500 mg tablet by mouth twice daily Tramadol 50 mg tablet by mouth every 6 hours as needed for chronic pain Lisinopril 10 mg tablet by mouth once daily
KP is a 43-year-old female with a PMH significant for type II diabetes mellitus, hypertension, major depressive disorder, chronic pain, and seasonal allergies presents to clinic after undergoing pharmacogenomic testing. Which medication(s) is KP currently taking that inhibit CYP2D6? Current Medications: Acetaminophen 650 mg tablet by mouth every 6 hours as needed Bupropion 24-hour extended-release (Wellbutrin XL) 300 mg tablet by mouth once daily Loratadine 10 mg tablet by mouth once daily Metformin 500 mg tablet by mouth twice daily Tramadol 50 mg tablet by mouth every 6 hours as needed for chronic pain Lisinopril 10 mg tablet by mouth once daily
Indicate if the following statement is true or false: “Competitive inhibition occurs when both, substrate and inhibitor compete for the same site of the enzyme.”
Indicate if the following statement is true or false: “Competitive inhibition occurs when both, substrate and inhibitor compete for the same site of the enzyme.”
A prodrug X is completely metabolized to its single active metabolite via CYP2C19 enzyme. What would you expect if another drug Y, which is a potent CYP2C19 inhibitor, is concomitantly administered to a patient on drug X? Please assume that therapeutic outcome is dependent on concentration of active metabolite of drug X.
A prodrug X is completely metabolized to its single active metabolite via CYP2C19 enzyme. What would you expect if another drug Y, which is a potent CYP2C19 inhibitor, is concomitantly administered to a patient on drug X? Please assume that therapeutic outcome is dependent on concentration of active metabolite of drug X.
Which of the following would you expect in N-acetyltransferase-2 (NAT2) rapid (or fast) acetylators compared to slow acetylators?
Which of the following would you expect in N-acetyltransferase-2 (NAT2) rapid (or fast) acetylators compared to slow acetylators?
Which is the most accurate definition that differentiates pharmacogenetics from pharmacogenomics?
Which is the most accurate definition that differentiates pharmacogenetics from pharmacogenomics?
A patient with decreased CYP2C19 enzyme activity is prescribed a prodrug that requires CYP2C19 for activation. What is the most likely consequence?
A patient with decreased CYP2C19 enzyme activity is prescribed a prodrug that requires CYP2C19 for activation. What is the most likely consequence?
A patient is identified as having a genetic polymorphism that results in increased activity of a drug-metabolizing enzyme. How might this affect the dosing of a drug that is normally inactivated by this enzyme?
A patient is identified as having a genetic polymorphism that results in increased activity of a drug-metabolizing enzyme. How might this affect the dosing of a drug that is normally inactivated by this enzyme?
Which type of genetic polymorphism is least likely to have a direct effect on protein structure or function?
Which type of genetic polymorphism is least likely to have a direct effect on protein structure or function?
What is the primary clinical implication of a patient being identified as a poor metabolizer for an enzyme that metabolizes an active drug to an inactive metabolite?
What is the primary clinical implication of a patient being identified as a poor metabolizer for an enzyme that metabolizes an active drug to an inactive metabolite?
A patient is prescribed a drug that is a substrate of CYP3A4. If the patient is also taking St. John's Wort, what is the expected interaction?
A patient is prescribed a drug that is a substrate of CYP3A4. If the patient is also taking St. John's Wort, what is the expected interaction?
A patient taking warfarin has a CYP2C9*2/3 genotype. What is the likely impact on their warfarin dosing requirements compared to a patient with CYP2C91/*1?
A patient taking warfarin has a CYP2C9*2/3 genotype. What is the likely impact on their warfarin dosing requirements compared to a patient with CYP2C91/*1?
A patient's drug response changes significantly after starting a new medication. This is determined to be due to a drug-drug interaction altering the patient's drug metabolizing enzyme activity. What is this phenomenon called?
A patient's drug response changes significantly after starting a new medication. This is determined to be due to a drug-drug interaction altering the patient's drug metabolizing enzyme activity. What is this phenomenon called?
A drug is metabolized by an enzyme that exhibits genetic polymorphism. If a patient has a genetic variation that results in decreased enzyme activity, how might this impact drug clearance?
A drug is metabolized by an enzyme that exhibits genetic polymorphism. If a patient has a genetic variation that results in decreased enzyme activity, how might this impact drug clearance?
A patient of African American descent is prescribed a drug primarily metabolized by CYP3A5. Considering that CYP3A5 expressers are more common in African Americans, how might this influence initial dosing considerations compared to a Caucasian patient?
A patient of African American descent is prescribed a drug primarily metabolized by CYP3A5. Considering that CYP3A5 expressers are more common in African Americans, how might this influence initial dosing considerations compared to a Caucasian patient?
A patient is identified as a poor metabolizer for DPYD before starting on 5-FU chemotherapy. What is the most critical clinical consideration related to this pharmacogenetic finding?
A patient is identified as a poor metabolizer for DPYD before starting on 5-FU chemotherapy. What is the most critical clinical consideration related to this pharmacogenetic finding?
A patient is prescribed irinotecan. Which genetic variation in UGT1A1 is most likely to result in increased toxicity?
A patient is prescribed irinotecan. Which genetic variation in UGT1A1 is most likely to result in increased toxicity?
A patient is starting isoniazid for tuberculosis treatment. Which NAT2 acetylator phenotype is most likely to experience peripheral neuropathy?
A patient is starting isoniazid for tuberculosis treatment. Which NAT2 acetylator phenotype is most likely to experience peripheral neuropathy?
Why is TPMT genetic testing important before initiating azathioprine treatment?
Why is TPMT genetic testing important before initiating azathioprine treatment?
A patient is taking drug A, an active drug metabolized by CYP2D6 into an inactive metabolite. If a CYP2D6 inducer is added to their medication regimen, what is the expected effect on drug A?
A patient is taking drug A, an active drug metabolized by CYP2D6 into an inactive metabolite. If a CYP2D6 inducer is added to their medication regimen, what is the expected effect on drug A?
A patient is prescribed codeine for pain relief. What CYP2D6 phenotype would raise significant concerns regarding the drug's effectiveness?
A patient is prescribed codeine for pain relief. What CYP2D6 phenotype would raise significant concerns regarding the drug's effectiveness?
A patient taking drug X, which is metabolized by CYP2C19, experiences elevated plasma concentrations of drug X after starting fluoxetine. What is the most likely explanation?
A patient taking drug X, which is metabolized by CYP2C19, experiences elevated plasma concentrations of drug X after starting fluoxetine. What is the most likely explanation?
A patient is found to have a CYP2A6*4/*4 genotype. What is the expected effect on nicotine metabolism?
A patient is found to have a CYP2A6*4/*4 genotype. What is the expected effect on nicotine metabolism?
A patient taking efavirenz is identified as a CYP2B6 ultra-rapid metabolizer. How might this genetic variation influence the effectiveness of efavirenz treatment?
A patient taking efavirenz is identified as a CYP2B6 ultra-rapid metabolizer. How might this genetic variation influence the effectiveness of efavirenz treatment?
A patient taking the CYP2C8 substrate rosiglitazone also starts taking rifampin. What is the expected interaction, and how might it affect rosiglitazone's efficacy?
A patient taking the CYP2C8 substrate rosiglitazone also starts taking rifampin. What is the expected interaction, and how might it affect rosiglitazone's efficacy?
A patient with a known CYP2C9 polymorphism is prescribed phenytoin. What is the most relevant consideration regarding this drug-gene interaction?
A patient with a known CYP2C9 polymorphism is prescribed phenytoin. What is the most relevant consideration regarding this drug-gene interaction?
A patient taking drug A also starts taking drug B. After this addition, the AUC of drug A increases significantly. Drug A is metabolized by CYP2D6, but not transported by P-gp. Drug B is a CYP2D6 inhibitor. This is an example of what kind of interaction?
A patient taking drug A also starts taking drug B. After this addition, the AUC of drug A increases significantly. Drug A is metabolized by CYP2D6, but not transported by P-gp. Drug B is a CYP2D6 inhibitor. This is an example of what kind of interaction?
In the context of therapeutic drug monitoring, which measurement is most useful for determining whether drug concentrations are within the desired range for efficacy and safety?
In the context of therapeutic drug monitoring, which measurement is most useful for determining whether drug concentrations are within the desired range for efficacy and safety?
Which type of genetic change is most likely to result in complete loss of function of a drug-metabolizing enzyme?
Which type of genetic change is most likely to result in complete loss of function of a drug-metabolizing enzyme?
For a prodrug that is metabolized by CYP2C19 to its active form, what is the expected effect of a CYP2C19 no-function allele on the drug's efficacy?
For a prodrug that is metabolized by CYP2C19 to its active form, what is the expected effect of a CYP2C19 no-function allele on the drug's efficacy?
A patient is prescribed a drug that has a narrow therapeutic window. What is the most important consideration regarding their drug levels?
A patient is prescribed a drug that has a narrow therapeutic window. What is the most important consideration regarding their drug levels?
CYP2C19*2 and *3 alleles are associated with which phenotype?
CYP2C19*2 and *3 alleles are associated with which phenotype?
Which of the following are key aspects of translating a patient's genotype into a predicted phenotype for a drug-metabolizing enzyme?
Which of the following are key aspects of translating a patient's genotype into a predicted phenotype for a drug-metabolizing enzyme?
What is the most likely consequence of a no function or decreased function allele on the AUC of an active parent drug?
What is the most likely consequence of a no function or decreased function allele on the AUC of an active parent drug?
How might genetic information impact the magnitude of drug-drug interactions?
How might genetic information impact the magnitude of drug-drug interactions?
Which population is more likely to have the CYP2A6*4 allele, and what effect does this likely have on nicotine metabolism?
Which population is more likely to have the CYP2A6*4 allele, and what effect does this likely have on nicotine metabolism?
Given that codeine is a prodrug activated by CYP2D6, which of the following CYP2D6 phenotypes would result in decreased analgesic relief as compared to a normal metabolizer?
Given that codeine is a prodrug activated by CYP2D6, which of the following CYP2D6 phenotypes would result in decreased analgesic relief as compared to a normal metabolizer?
The data in the table below were obtained in a pharmacokinetic study of a drug that is predominately metabolized by UGT1A1 to a single inactive metabolite. The subjects were separated into groups based on UGT1A1*28 genotype. Cmax and AUC for the parent compound were shown in the table below. Which group has the lowest enzyme activity?
The data in the table below were obtained in a pharmacokinetic study of a drug that is predominately metabolized by UGT1A1 to a single inactive metabolite. The subjects were separated into groups based on UGT1A1*28 genotype. Cmax and AUC for the parent compound were shown in the table below. Which group has the lowest enzyme activity?
Dr. P wants to learn about CYP2C19 and PPIs, and how to implement pharmacogenomics in the adult outpatient care clinic. What is the best online database that Dr. P could use in order to gather information on the CYP2C19 gene, the pathways involving CYP2C19 and PPIs, as well as clinical pharmacogenomic dosing tables and dosing guidelines if available?
Dr. P wants to learn about CYP2C19 and PPIs, and how to implement pharmacogenomics in the adult outpatient care clinic. What is the best online database that Dr. P could use in order to gather information on the CYP2C19 gene, the pathways involving CYP2C19 and PPIs, as well as clinical pharmacogenomic dosing tables and dosing guidelines if available?
Which of the following statements is true regarding the CYP2C19 enzyme?
Which of the following statements is true regarding the CYP2C19 enzyme?
A patient with chronic pain is treated with tramadol and is genotyped for CYP2D6. The diplotype indicates the patient has a CYP2D6*1/*1 activity score. Which range corresponds to this patient's likely activity score?
A patient with chronic pain is treated with tramadol and is genotyped for CYP2D6. The diplotype indicates the patient has a CYP2D6*1/*1 activity score. Which range corresponds to this patient's likely activity score?
What CYP enzyme has gene duplication and is likely associated with an increased risk of toxicity from standard doses of codeine?
What CYP enzyme has gene duplication and is likely associated with an increased risk of toxicity from standard doses of codeine?
Which of the following CYP enzymes has been identified with gene duplication?
Which of the following CYP enzymes has been identified with gene duplication?
Genetic variation in which of the following enzymes is associated with decreased formation of the active metabolite from clopidogrel, requiring an alternative for antiplatelet therapy?
Genetic variation in which of the following enzymes is associated with decreased formation of the active metabolite from clopidogrel, requiring an alternative for antiplatelet therapy?
A patient who has difficulty obtaining analgesic effects from what prodrug medication has a homozygous genetic mutation in CYP2D6?
A patient who has difficulty obtaining analgesic effects from what prodrug medication has a homozygous genetic mutation in CYP2D6?
A patient is prescribed a drug, omeprazole, that is exclusively metabolized to the metabolite 5-hydroxyomeprazole by CYP2C19. The ratio of omeprazole to the metabolite 5-hydroxyomeprazole (OMP/5OH-OMP) has frequently been used as an index of CYP2C19 activity. If the patient takes a medication that induces the CYP2C19 enzyme, what happens to the OMP/5OH-OMP ratio?
A patient is prescribed a drug, omeprazole, that is exclusively metabolized to the metabolite 5-hydroxyomeprazole by CYP2C19. The ratio of omeprazole to the metabolite 5-hydroxyomeprazole (OMP/5OH-OMP) has frequently been used as an index of CYP2C19 activity. If the patient takes a medication that induces the CYP2C19 enzyme, what happens to the OMP/5OH-OMP ratio?
If a patient is identified as an intermediate metabolizer, how would you expect this to affect a drug that's normally metabolized into an inactive compound?
If a patient is identified as an intermediate metabolizer, how would you expect this to affect a drug that's normally metabolized into an inactive compound?
What is the likely consequence of a non-synonymous genetic polymorphism?
What is the likely consequence of a non-synonymous genetic polymorphism?
A patient is prescribed a medication. The medication is an active drug that is metabolized by an enzyme into an inactive metabolite at a standard rate. What would happen if a patient had decreased enzyme activity due to a genetic variation and they take the same medication?
A patient is prescribed a medication. The medication is an active drug that is metabolized by an enzyme into an inactive metabolite at a standard rate. What would happen if a patient had decreased enzyme activity due to a genetic variation and they take the same medication?
If a patient is a poor metabolizer (PM), what is the expected effect on a prodrug?
If a patient is a poor metabolizer (PM), what is the expected effect on a prodrug?
A drug is within the therapeutic window for a patient. If the patient's drug concentration rises above the therapeutic window, how will that affect the patient?
A drug is within the therapeutic window for a patient. If the patient's drug concentration rises above the therapeutic window, how will that affect the patient?
If a patient's genotype indicates increased enzyme activity, how would you expect this to affect a drug's Area Under the Curve (AUC)?
If a patient's genotype indicates increased enzyme activity, how would you expect this to affect a drug's Area Under the Curve (AUC)?
A patient is taking bupropion and requires pain relief. Why is this important to consider regarding tramadol?
A patient is taking bupropion and requires pain relief. Why is this important to consider regarding tramadol?
A patient's genetic test reveals they have a decreased function allele for a drug-metabolizing enzyme. How will that impact the drug's clearance?
A patient's genetic test reveals they have a decreased function allele for a drug-metabolizing enzyme. How will that impact the drug's clearance?
A patient is taking clopidogrel. What will happen if they have no CYP2C19 enzyme activity?
A patient is taking clopidogrel. What will happen if they have no CYP2C19 enzyme activity?
A patient is prescribed codeine. The CYP2D6 enzyme is responsible for converting codeine into morphine. What is the effect of being an ultra-rapid metabolizer with a 2D6 duplication?
A patient is prescribed codeine. The CYP2D6 enzyme is responsible for converting codeine into morphine. What is the effect of being an ultra-rapid metabolizer with a 2D6 duplication?
Flashcards
Pharmacogenomics
Pharmacogenomics
The study of how genes affect a person's response to drugs.
Pharmacogenetics
Pharmacogenetics
Examines a single gene-drug interaction and how variations in that gene impact the response to a drug or drug class.
Genetic Polymorphisms
Genetic Polymorphisms
Variations in DNA sequences that can alter enzyme activity, impacting drug pharmacokinetics and pharmacodynamics.
Phase I Enzymes
Phase I Enzymes
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CYP2A6*4
CYP2A6*4
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CYP2A6 Clinical Significance
CYP2A6 Clinical Significance
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CYP2B6 Clinical Significance
CYP2B6 Clinical Significance
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CYP2C8 Clinical Significance
CYP2C8 Clinical Significance
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CYP2C9 Clinical Significance
CYP2C9 Clinical Significance
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No/Decreased Function Allele - Parent Drug
No/Decreased Function Allele - Parent Drug
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No/Decreased Function Allele - Metabolite(s)
No/Decreased Function Allele - Metabolite(s)
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Increased Function Allele - Parent Drug
Increased Function Allele - Parent Drug
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Increased Function Allele - Metabolite(s)
Increased Function Allele - Metabolite(s)
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Phenoconversion
Phenoconversion
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Genetic Variation by Race
Genetic Variation by Race
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Therapeutic Window
Therapeutic Window
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Phenotype Terminology
Phenotype Terminology
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Prodrug
Prodrug
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CYP2C19 Clinical Significance
CYP2C19 Clinical Significance
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Codeine & Tramadol: CYP2D6
Codeine & Tramadol: CYP2D6
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Voriconazole Clearance
Voriconazole Clearance
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Intermediate Metabolizers
Intermediate Metabolizers
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PharmGKB
PharmGKB
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N-acetyltransferase-2
N-acetyltransferase-2
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Study Notes
- Pharmacogenomics studies the effects of genes on drug response.
- Pharmacogenetics studies how variations in a single gene affect drug response.
Impact of Genetic Polymorphisms
- Genetic variations affecting drug targets, transporters, and metabolizing enzymes, influence pharmacokinetics (body's effect on the drug) and pharmacodynamics (drug's effect on the body).
- Drug-metabolizing enzymes influence metabolism.
- Transporters influence drug distribution.
- Normal enzyme activity leads to typical drug concentrations.
- Decreased enzyme activity can lead to more active drug, increasing side effects, or less active metabolite, decreasing sensitivity.
- Increased enzyme activity might lead to less active drug or more active metabolite.
- Key considerations for gene-drug relationships involve understanding the impact on the active drug (parent medication or metabolite), changes in drug exposure (increased or decreased), and the resulting clinical impact.
- Genetic polymorphisms can have varied consequences.
- Synonymous polymorphisms have no consequence, due to a change in the base pair, but the codon and protein remain the same.
- Non-synonymous polymorphisms lead to a change in a different amino acid, also known as missense SNPs.
- Premature Stop Codons, or nonsense polymorphisms, are caused by an insertion that creates a premature stop codon.
Active Drug to Inactive Metabolite
- Normal enzyme activity results in usual drug concentrations.
- Decreased enzyme activity results in more active drug which increases risk of side effects.
Prodrug to Active Metabolite
- Normal enzyme activity causes normal metabolism to active metabolite.
- Decreased enzyme activity results in less active metabolite, leading to lower concentrations and decreased sensitivity.
Phenotype Terminology
- Allele to Phenotype is described as allele to genotype (or diplotype) to phenotype.
- Organizations like CPIC are standardizing phenotype definitions for pharmacogenetics.
- Drug metabolizing enzyme phenotypes are standardized.
- Reference is normal metabolizers.
- Translation tables identify variations.
Drug Metabolizing Enzyme Phenotypes
- Normal metabolizers are the reference.
- Rapid/Ultra-rapid metabolizers exhibit increased enzyme activity.
- Intermediate metabolizers exhibit little to no activity.
- Poor metabolizers exhibit little to no activity, influenced by the specific gene.
Clinical Consequences of Genetic Variation
- Genetic variations can increase or decrease drug exposure.
- The therapeutic window lies between effectiveness and toxicity.
- Subtherapeutic results occur below the line of effectiveness.
- More side effects occur above the line of toxicity.
- Increased Area Under the Curve (AUC) signifies increased drug exposure.
- Tmax (the time at which the observed drug concentration is the highest) can be affected by Genetic variation.
- Ideal Drug Concentration and Response features higher drug concentrations leading to higher drug response, within toxicity and effectiveness levels.
- Resistance features high drug concentrations, with no drug effectiveness.
- Sensitivity features Lower drug concentrations, and a higher response.
Phenoconversion
- Phenoconversion occurs when a phenotype based on genetics changes due to drug interactions and genetics.
- Sequence2Script gives prescribing recommendations based on patient information.
- Bupropion, a CYP2D6 inhibitor, may necessitate treating patients taking it as poor metabolizers for tramadol.
Impact of Genetic Information on Drug-Drug Interactions
- The FDA identifies increased drug concentration as an "actionable annotation" when CYP2D6 poor metabolizers take duloxetine and fluvoxamine (a 1A2 inhibitor) together.
- CYP1A2 and CYP2D6 are responsible.
- 1A2 inhibition is clinically relevant in drug interactions, notably in CYP2D6 poor metabolizers.
Notable Genetic Variation by Race
- SNPs and functional SNPs can vary in different ancestral populations.
- Frequency tables display allele-level frequencies.
Substrates Metabolized into Active Metabolites
- Clopidogrel, a prodrug, is activated by CYP2C19.
- Patients lacking CYP2C19 enzyme activity risk secondary heart attacks due to the drug's ineffectiveness.
Specific Phase I Enzymes
- Phase I enzymes are crucial for drug metabolism, and genetic variations in these enzymes can significantly affect drug efficacy and toxicity.
CYP2A6
- Gene duplication is possible.
- CYP2A6*4 signifies gene deletion, indicating no function.
- PM Phenotype is more common in Asian populations when compared to Caucasian populations.
- The substrate is Nicotine.
- Genetic variations can affect nicotine metabolism, influencing smoking behavior and cessation therapy response.
- Polymorphisms can alter nicotine metabolism, affecting smoking behaviors and cessation treatments.
CYP2B6
- Phenotypes: PM, IM, NM, RM, UM.
- Substrates: Efavirenz, methadone, sertraline.
- Inhibitor: Sertraline.
- Inducers: Efavirenz, rifampin, carbamazepine.
- Variations can affect the metabolism of efavirenz, methadone, and sertraline.
CYP2C8
- Polymorphic.
- Variants are in strong Linkage Disequilibrium (LD) with CYP2C9.
- Substrates: Glitazones (rosiglitazone, pioglitazone), ibuprofen.
- Inhibitor: Ibuprofen.
- Inducer: Rifampin.
- Variations impact glitazones (diabetes) and ibuprofen (NSAID) metabolism.
CYP2C9
- Know the difference in biochemical and clinical function for *2 and *3 alleles.
- Phenotypes: PM, IM, NM.
- Uses activity score translation (no memorization needed for Activity Score (AS) to phenotype definitions).
- Substrates: Warfarin, phenytoin, NSAIDs (ibuprofen).
- Inhibitors: Amiodarone, fluconazole.
- Inducer: Rifampin.
- Crucial for warfarin metabolism; variations affect required therapeutic anticoagulation dose.
- The *2 and *3 alleles have reduced enzyme activity, leading to decreased metabolism of CYP2C9 substrates.
CYP2C19
- *2 and *3 alleles: No function.
- *17 allele: Increased function.
- PM is more common in Asian populations.
- Phenotypes: PM, IM, NM, RM, UM.
- Substrates: Clopidogrel, PPIs (omeprazole), select SSRIs, voriconazole.
- Inhibitors: Fluvoxamine, fluoxetine.
- Inducer: Rifampin.
- Clopidogrel is activated by CYP2C19, so individuals lacking CYP2C19 enzyme activity are at high risk of secondary heart attack because the drug will be ineffective.
- The FDA includes guidance on pharmacogenetic tests for CYP2C19 in drug labels, and alternative treatments should be considered for CYP2C19 poor metabolizers.
CYP2D6
- Phenotypes: PM, IM, NM, UM.
- Uses activity score, duplication (CNV) possible.
- Substrates: Codeine, tramadol, paroxetine, duloxetine.
- Inhibitors: Bupropion, fluvoxamine, paroxetine, quinidine.
- Inducers: None (not inducible).
- Codeine and Tramadol are prodrugs that require CYP2D6 activity for conversion to active metabolites, and poor metabolizers may not achieve pain relief.
- Phenoconversion occurs when Bupropion, a CYP2D6 inhibitor, alters tramadol metabolism.
CYP3A4/5
- CYP3A4*22 is emerging as a clinically relevant variant.
- For CYP3A5: *1 is a functional variant conferring expresser phenotype (NM or IM).
- CYP3A5*3 is no function, and if homozygous, confers non-expresser phenotype or PM.
- Expressers are more common in African Americans.
- Substrates: Tacrolimus, quetiapine, verapamil.
- Inhibitor: Ketoconazole.
- Inducers: Rifampin, St. John’s wort.
- Variations affect the metabolism of many drugs and contribute to severe drug responses.
DPYD
- Highly polymorphic.
- Variants are rare with low population frequency but have severe clinical consequences.
- Substrates: Fluoropyrimidines (5-FU and capecitabine).
- Variations can lead to decreased enzyme activity, resulting in more active drug and increasing side effects.
UGT1A1
- UGT1A1*28 / poor metabolizers are frequent in African Americans.
- Phenotypes: PM, IM, NM.
- Substrates: Bilirubin, Irinotecan (UGT1A1 metabolizes active metabolite)
- Inducer: Rifampin
NAT2
- PMs = slow acetylators
- IMs and NMs = fast acetylators
- Substrates: Isoniazid, hydralazine, amifampridine
TPMT
- Phenotypes include: PM, IM, NM.
- Low variation frequency, however, the clinical consequences are severe.
- Substrates: Thiopurines (azathioprine, 6-mercaptopurine).
NUDT15
- Phenotypes include: PM, IM, NM.
- Substrates: Thiopurines (azathioprine, 6-mercaptopurine).
COMT
- Variation exists; evidence is mixed for clinical utility.
- Substrates: Catecholamine neurotransmitters.
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