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Questions and Answers
Which of the following drugs is NOT a substrate of CYP2D6?
Which of the following drugs is NOT a substrate of CYP2D6?
What is a consequence of poor metabolizers (PMs) taking tamoxifen?
What is a consequence of poor metabolizers (PMs) taking tamoxifen?
What therapeutic effect is primarily achieved by the active metabolite of codeine?
What therapeutic effect is primarily achieved by the active metabolite of codeine?
Which of the following patients is likely to experience increased risks from tramadol due to high concentrations of its active metabolite?
Which of the following patients is likely to experience increased risks from tramadol due to high concentrations of its active metabolite?
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CYP1A2 is involved in the metabolism of which of the following?
CYP1A2 is involved in the metabolism of which of the following?
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Which effect is associated with ultrarapid metabolizers (UMs) in terms of drug metabolism?
Which effect is associated with ultrarapid metabolizers (UMs) in terms of drug metabolism?
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What impact does decreased metabolism have for medications like carvedilol in poor metabolizers?
What impact does decreased metabolism have for medications like carvedilol in poor metabolizers?
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Which of these statements about CYP2D6 and antidepressants is true?
Which of these statements about CYP2D6 and antidepressants is true?
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What is the primary function of cytochrome P450 enzymes?
What is the primary function of cytochrome P450 enzymes?
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Which metabolizer type has significantly reduced or non-functional enzyme activity?
Which metabolizer type has significantly reduced or non-functional enzyme activity?
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How can genetic polymorphisms in the CYP450 enzyme system affect drug therapy?
How can genetic polymorphisms in the CYP450 enzyme system affect drug therapy?
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Which of the following is a consequence of genetic polymorphism in drug metabolism?
Which of the following is a consequence of genetic polymorphism in drug metabolism?
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What are the major families of cytochrome P450 enzymes primarily involved in drug metabolism?
What are the major families of cytochrome P450 enzymes primarily involved in drug metabolism?
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What is a potential risk for individuals who are poor metabolizers of a drug?
What is a potential risk for individuals who are poor metabolizers of a drug?
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Which CYP450 enzyme is primarily responsible for metabolizing the majority of clinically important drugs?
Which CYP450 enzyme is primarily responsible for metabolizing the majority of clinically important drugs?
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How do genetic polymorphisms in the CYP450 enzyme system impact individualized medicine?
How do genetic polymorphisms in the CYP450 enzyme system impact individualized medicine?
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What characterizes rapid or ultra-rapid metabolizers (RM)?
What characterizes rapid or ultra-rapid metabolizers (RM)?
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How can variations in CYP enzymes influence drug interactions?
How can variations in CYP enzymes influence drug interactions?
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What risk is associated with certain CYP polymorphisms?
What risk is associated with certain CYP polymorphisms?
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Which CYP enzyme is noted for metabolizing approximately 15–20% of prescribed drugs?
Which CYP enzyme is noted for metabolizing approximately 15–20% of prescribed drugs?
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What is the primary benefit of understanding an individual's CYP genotype in medicine?
What is the primary benefit of understanding an individual's CYP genotype in medicine?
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Which drug is NOT metabolized by CYP2C9?
Which drug is NOT metabolized by CYP2C9?
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What impact do polymorphisms in CYP enzymes have on hormone levels?
What impact do polymorphisms in CYP enzymes have on hormone levels?
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Polymorphisms in CYP enzymes have been linked to increased risk of which condition?
Polymorphisms in CYP enzymes have been linked to increased risk of which condition?
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What is a possible consequence of using S-warfarin in poor metabolizers?
What is a possible consequence of using S-warfarin in poor metabolizers?
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Which alleles are identified as significant coding variants of CYP2C9?
Which alleles are identified as significant coding variants of CYP2C9?
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What is a consequence of CYP2C19 polymorphism when using diazepam?
What is a consequence of CYP2C19 polymorphism when using diazepam?
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How does the CYP2C9*3 allele affect warfarin dose requirements?
How does the CYP2C9*3 allele affect warfarin dose requirements?
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Which drug's effectiveness may be decreased in extensive metabolizers due to CYP2C19 activity?
Which drug's effectiveness may be decreased in extensive metabolizers due to CYP2C19 activity?
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What type of drug is affected by CYP2D6 polymorphism?
What type of drug is affected by CYP2D6 polymorphism?
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What is a potential risk when using phenytoin in poor metabolizers?
What is a potential risk when using phenytoin in poor metabolizers?
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Which consequence is associated with the use of glimepiride in poor metabolizers?
Which consequence is associated with the use of glimepiride in poor metabolizers?
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What is the primary metabolic role of the CYP1A2*1A allele?
What is the primary metabolic role of the CYP1A2*1A allele?
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Individuals with inactive CYP2A6 are less likely to become smokers due to which of the following reasons?
Individuals with inactive CYP2A6 are less likely to become smokers due to which of the following reasons?
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Which enzyme is NOT involved in the metabolism of efavirenz?
Which enzyme is NOT involved in the metabolism of efavirenz?
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What is the role of UDP glucuronosyltransferases (UGTs) in drug metabolism?
What is the role of UDP glucuronosyltransferases (UGTs) in drug metabolism?
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Which of the following metabolic pathways is linked to the clearance of isoniazid?
Which of the following metabolic pathways is linked to the clearance of isoniazid?
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What implication does being a 'ultra-rapid metabolizer' (UM) have on nicotine addiction susceptibility?
What implication does being a 'ultra-rapid metabolizer' (UM) have on nicotine addiction susceptibility?
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Which enzyme is primarily responsible for detoxification of reactive species?
Which enzyme is primarily responsible for detoxification of reactive species?
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What role do sulfotransferases (SULTs) play in drug metabolism?
What role do sulfotransferases (SULTs) play in drug metabolism?
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Study Notes
Cytochrome P450 (CYP) Enzymes
- CYP Enzymes: Catalyze the oxidation of organic substances in the body including a key role in drug metabolism.
- Location: Primarily found in liver cells.
- Clinical Importance: Variability in CYP enzyme activity leads to differences in drug clearance and response.
- CYP Families: CYP1, CYP 2, and CYP 3 are involved in drug metabolism.
- Major Players: CYP2A6, CYP2B6, CYP2C9, CYP2C19 CYP2D6, CYP2E1, and CYP3A4 are responsible for metabolizing most drugs.
- Individual Variability: All individuals have different capabilities to metabolize drugs using a specific pathway.
Consequences of Genetic Polymorphism in Cytochrome P450 Enzyme System
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Variable Drug Metabolism: Results in varying drug effects based on how fast or slow the body metabolizes the drug.
- Poor Metabolizers (PM): Reduced or non-functional enzyme activity.
- Intermediate Metabolizer (IM): Low or reduced enzyme activity
- Extensive Metabolizer (EM): Normal enzyme activity.
- Rapid or Ultra-Rapid Metabolizer (RM): High enzyme activity.
- Drug Interactions: Variations in CYP enzymes can influence how individuals respond to drug interactions.
- Variability in Drug Response: Genetic differences can influence the response to drugs, leading to either enhanced or diminished therapeutic effects.
- Increased Risk of Adverse Drug Reactions: Certain polymorphisms can lead to a higher risk of adverse drug reactions.
- Altered Hormone Levels: CYP enzymes are involved in the metabolism of steroid hormones. Polymorphisms can influence hormone levels and affect hormone-related conditions.
- Impact on Disease Risk: Influences susceptibility to diseases through the metabolism of carcinogens, toxins, and other environmental factors.
- Individualized Medicine: Understanding an individual's CYP genotype can help personalize drug treatments to improve efficacy and reduce side effects.
Pharmacogenomics of CYP2C9
- Most Abundant Enzyme: CYP2C9 is the most expressed enzyme in the human liver and accounts for the metabolism of approximately 15–20% of prescribed and over-the-counter drugs.
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Drugs Metabolized: CYP2C9 metabolizes several clinically important drugs, including:
- Antidiabetic drugs (tolbutamide and glipizide)
- Anticonvulsant (phenytoin)
- Anticoagulant (warfarin)
- Antihypertensive drug (losartan)
- Diuretic (torasemide)
- Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, diclofenac, piroxicam, tenoxicam, and mefenamic acid.
- Clinical Relevance: The clinical relevance of CYP2C9 polymorphisms was initiated and identified by two main coding variants, CYP2C9*2 and *3 Alleles.
- Common Reduced-Function Variants: CYP2C9*2 (rs1799853) and *3 (rs1057910) alleles reduce warfarin clearance by 30% and 90% respectively, which translates into 19% and 33% reductions per allele in warfarin dosage requirements compared to noncarriers.
Pharmacogenomics of CYP2C19
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Clinical Importance: CYP2C19 is a clinically important enzyme that metabolizes several drugs, including:
- Antiulcer drug (omeprazole)
- Anticonvulsant (mephenytoin)
- Antimalarial (proguanil)
- Anxiolytic drug (diazepam)
- Certain antidepressants (citalopram, imipramine, amitriptyline, and clomipramine).
CYP2D6 Polymorphism
- High Polymorphism: CYP2D6 is one of the most polymorphic CYP450, metabolizing approximately 20% of prescribed drugs.
Pharmacogenomics of CYP1A2
- Coffee Metabolism: CYP1A2 is involved in the metabolism of coffee, estrogen, clozapine, theophylline, olanzapine, and certain procarcinogens.
- Enhanced Induction: Increased induction of this enzyme can lead to altered therapeutic outcomes or an increased risk of certain cancers.
- Caffeine Metabolism: Coffee is a major source of caffeine, which is metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme.
- Genetic Variation: Individuals who are homozygous for the CYP1A21A allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A21F are "slow" caffeine metabolizers.
Pharmacogenomics of CYP2B6
- Drug Metabolism: CYP2B6 is involved in the metabolism of bupropion, efavirenz, nevirapine, cyclophosphamide, and ifosfamide.
- Central Nervous System (CNS): Many HIV patients receiving efavirenz experience CNS side effects, which are suggested to be from the varying concentration of efavirenz in plasma.
Pharmacogenomics of CYP2A6
- Nicotine Metabolism: CYP2A6 metabolizes nicotine, cotinine (nicotine metabolites), methyl-n-amylnitrosamine (MNAN) - a potential carcinogen, and nicotine-derived nitrosamine ketone (NNK).
- Nicotine Addiction: Individuals who have ultra-rapid metabolizers (UMs) experience a reduced nicotine metabolism and are less likely to become smokers. If they do, they smoke fewer cigarettes per day.
- Smokers with Inactive CYP2A6: They experience increased levels of nicotine, leading to harmful side effects that discourage smoking initiation.
Role of Phase II Biotransformation in Drug Elimination
- Drug Conjugation Reactions: Several classes of phase II biotransformation enzymes catalyze drug conjugation reactions.
- Important Enzymes: UDP glucuronosyltransferases (UGTs), sulfotransferases (SULTs), Nacetyltransferases (NATs), glutathione Stransferases (GSTs), and thiopurine-S-methyltransferase (TPMT).
- Role in Drug Clearance: These enzymes contribute to most clearance pathways for most drugs.
- AcylCoA Synthetase Medium Chain Family Members: They act in conjunction with acylCoA: amino acid N-acyltransferases to generate amino acid conjugates.
- Catechol Omethyltransferase (COMT): It is functionally important in the clearance of neurotransmitters or other molecules of endogenous importance.
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