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Questions and Answers
Which of the following is NOT considered an external factor affecting biotransformation?
Which of the following is NOT considered an external factor affecting biotransformation?
What is the primary consequence of gene deletion in genetic polymorphism?
What is the primary consequence of gene deletion in genetic polymorphism?
Single nucleotide polymorphisms (SNPs) can affect all of the following EXCEPT:
Single nucleotide polymorphisms (SNPs) can affect all of the following EXCEPT:
How do SNPs in the promoter region typically influence gene expression?
How do SNPs in the promoter region typically influence gene expression?
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What is the role of the CYP2B6 enzyme in biotransformation?
What is the role of the CYP2B6 enzyme in biotransformation?
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Which of the following statements about CYP2D6 is TRUE?
Which of the following statements about CYP2D6 is TRUE?
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What is one effect of SNPs occurring in the coding region of a gene?
What is one effect of SNPs occurring in the coding region of a gene?
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What type of genetic polymorphism involves the removal of an entire segment of a gene?
What type of genetic polymorphism involves the removal of an entire segment of a gene?
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What is a significant effect of aging on glucuronidation related to ibuprofen?
What is a significant effect of aging on glucuronidation related to ibuprofen?
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How does pregnancy affect the activity of CYP1A2?
How does pregnancy affect the activity of CYP1A2?
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Which of the following statements best describes UGT enzyme levels in newborns?
Which of the following statements best describes UGT enzyme levels in newborns?
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What is the significance of the Km value in enzyme kinetics as it relates to acetaminophen?
What is the significance of the Km value in enzyme kinetics as it relates to acetaminophen?
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Which statement best reflects the effects of CYP3A levels in older adults?
Which statement best reflects the effects of CYP3A levels in older adults?
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Why is personalized medicine important in drug therapy?
Why is personalized medicine important in drug therapy?
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Which enzyme is associated with the highest capacity for metabolizing acetaminophen?
Which enzyme is associated with the highest capacity for metabolizing acetaminophen?
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What role does the molecular structure of a drug play in its metabolism?
What role does the molecular structure of a drug play in its metabolism?
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What is the primary function of the heme group in Cytochrome P450 enzymes?
What is the primary function of the heme group in Cytochrome P450 enzymes?
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How does the size of the substrate binding pocket influence the function of P450 enzymes?
How does the size of the substrate binding pocket influence the function of P450 enzymes?
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Which of the following components is NOT part of the nomenclature for CYP genes?
Which of the following components is NOT part of the nomenclature for CYP genes?
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What characteristic of P450 enzymes aids in the metabolism of hydrophobic drug molecules?
What characteristic of P450 enzymes aids in the metabolism of hydrophobic drug molecules?
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What factor contributes to the distinct substrate binding specificity among different P450 enzymes?
What factor contributes to the distinct substrate binding specificity among different P450 enzymes?
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What happens when a substrate binds to the pocket of a P450 enzyme?
What happens when a substrate binds to the pocket of a P450 enzyme?
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What is the primary role of flavin monooxygenases (FMOs) in drug metabolism?
What is the primary role of flavin monooxygenases (FMOs) in drug metabolism?
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In terms of enzyme classification, what does a digit following the CYP designation indicate?
In terms of enzyme classification, what does a digit following the CYP designation indicate?
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Which of the following statements accurately describes a difference between FMOs and P450 enzymes?
Which of the following statements accurately describes a difference between FMOs and P450 enzymes?
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What type of reactions do P450 enzymes mainly catalyze in drug metabolism?
What type of reactions do P450 enzymes mainly catalyze in drug metabolism?
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What substrates do dehydrogenases typically metabolize?
What substrates do dehydrogenases typically metabolize?
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What cofactor is exclusively required by monooxygenases?
What cofactor is exclusively required by monooxygenases?
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What consequence might occur in individuals with inefficient aldehyde dehydrogenase (ALDH)?
What consequence might occur in individuals with inefficient aldehyde dehydrogenase (ALDH)?
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Where are monoamine oxidases (MAOs) primarily located?
Where are monoamine oxidases (MAOs) primarily located?
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Which of the following enzymes acts on alcohol and does not require molecular oxygen?
Which of the following enzymes acts on alcohol and does not require molecular oxygen?
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What type of reaction does monoamine oxidase (MAO) catalyze?
What type of reaction does monoamine oxidase (MAO) catalyze?
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What type of glucuronides are formed from phenols and alcohols?
What type of glucuronides are formed from phenols and alcohols?
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Which of the following drug molecules can undergo C-glucuronidation?
Which of the following drug molecules can undergo C-glucuronidation?
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What product results from morphine O-glucuronidation that contributes to pain relief?
What product results from morphine O-glucuronidation that contributes to pain relief?
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Which of the following is a potential consequence of unstable glucuronide formation?
Which of the following is a potential consequence of unstable glucuronide formation?
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What is the co-substrate required for sulfonation reactions?
What is the co-substrate required for sulfonation reactions?
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Which of the following is true regarding N-glucuronidation?
Which of the following is true regarding N-glucuronidation?
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What characterizes the products formed from carboxylic acids during glucuronidation?
What characterizes the products formed from carboxylic acids during glucuronidation?
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What type of glucuronides is more common in humans compared to lab animals?
What type of glucuronides is more common in humans compared to lab animals?
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What does acetylation introduce to the drug molecule?
What does acetylation introduce to the drug molecule?
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Which enzyme is primarily responsible for catalyzing the acetylation of amines?
Which enzyme is primarily responsible for catalyzing the acetylation of amines?
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What is a key characteristic that differentiates acetylation from other phase II reactions?
What is a key characteristic that differentiates acetylation from other phase II reactions?
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Which amino acid is typically involved in forming amino acid conjugates during phase II metabolism?
Which amino acid is typically involved in forming amino acid conjugates during phase II metabolism?
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What is the first step in the amino acid conjugation process?
What is the first step in the amino acid conjugation process?
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What is the role of acyl-coenzyme A ligase in amino acid conjugation?
What is the role of acyl-coenzyme A ligase in amino acid conjugation?
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What effect does methylation have on water solubility?
What effect does methylation have on water solubility?
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Which of the following is true about NAT-2?
Which of the following is true about NAT-2?
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Study Notes
Module 4.1: Drug Metabolism (Biotransformation)
- Drug metabolism, also known as biotransformation, involves the conversion of a drug into metabolites.
- The goal of this module is to provide a comprehensive understanding of drug metabolism principles, drug-drug interactions, and genetic impacts on metabolism rates.
- Key terms in drug metabolism include xenobiotic, a foreign substance not used by the body for normal function, with examples like therapeutic drugs, herbal remedies and natural products.
The Fate of a Drug in the Body
- Drug administration involves dissolution (drug dissolving from its form), absorption (primarily in small intestine), distribution (drug circulation throughout body), metabolism (conversion to metabolites), and elimination (removal from body)
General Definition
- Rate of food digestion and energy production
- Conversion of a drug into metabolites.
- Synonymous with drug metabolism.
Importance of Drug Biotransformation
- Structural changes occur inside the body due to metabolism, which can inactivate the drug or produce toxic metabolites.
- Water solubility is improved by metabolism, leading to easier excretion.
- The duration of action of a drug is determined through its rate and extent of biotransformation.
How Drugs are Biotransformed
- Enzymes catalyze various reactions in the body, contributing to drug biotransformation.
- Rate and extent of biotransformation is influenced by several factors, such as drug structure.
- Not all drugs undergo biotransformation.
- Biotransformation isn't always required for drug activation.
Factors Influencing Drug Biotransformation
- Drug structure influences how it's transformed.
- Enzyme affinity for a drug determines if it's a substrate for that enzyme.
- Enzyme levels and metabolic rates vary between individuals.
- Availability of cofactors and co-substrates impact the effect.
- Presence of other xenobiotics, which can act as inhibitors, impacts drug metabolism.
Effects of Biotransformation
- Lipophilic drugs are converted to hydrophilic molecules for easier excretion.
- Active drugs can be transformed into inactive metabolites.
- Active drugs can potentially be converted into other active metabolites.
- Prodrugs are inactive compounds that are metabolized into active metabolites.
Phases of Biotransformation
- Phase 1 reactions involve simple transformations.
- Examples: oxidation, hydrolysis, reduction, dehalogenation, and dealkylation.
- Key enzyme involved is cytochrome P450.
- Phase 2 reactions involve conjugation with small molecules.
- Examples: glucuronidation, sulfonation, acetylation, amino acid conjugation, methylation, and fatty acid conjugation.
Sequence of Reactions
- Primary metabolite is the initial metabolite formed from a drug.
- Secondary metabolite is formed from further metabolism of a primary metabolite
- Phase 1 reactions do not always precede Phase 2 reactions
Substrate Specificity of Biotransformation Enzymes
- Biotransformation enzymes have broad substrate specificity.
- This wide range is an advantage for eliminating a variety of toxins.
Factors Affecting Drug Disposition
- Route of administration influences the drug's journey.
- Interactions with transporter proteins impact drug transit across cell membranes.
- Drug biotransformation chemically modifies a drug in the body.
- The amount of drug administered determines the subsequent effects of that drug.
Sites of Drug Biotransformation
- Liver is the primary site for drug biotransformation.
- Upper intestine involved with orally administered drugs, during absorption.
Systemic Circulation and Presystemic Biotransformation
- Systemic circulation refers to the bloodstream after a drug passes through the liver.
- Presystemic biotransformation is the metabolism of drugs occurring before entering the systemic circulation.
- This is significant when administering orally as a notable portion is metabolized in the gastrointestinal (GI) tract and liver.
Enterohepatic Cycling
- Recirculation of drugs and metabolites between the liver and intestines.
- Drugs are absorbed from the intestines and transported to the liver.
- Metabolized drugs are then transported to the gallbladder.
- Drugs are released back into the intestines, and metabolites are reabsorbed, extending the drug's presence in the body.
Rate of Drugs in the Body
- Majority of drugs are eliminated through metabolism.
- Some amount is excreted through renal and biliary pathways.
Factors Affecting Drug Biotransformation
- Drug structure, enzyme amount, enzyme affinity for drugs, availability of cofactors and co-substrates, presence of other drugs.
Common Functional Groups in Drugs and Their Metabolism
- Drugs contain various functional groups susceptible to enzymatic modification.
- Examples: amines, cyclohexyl or alkyl chains, aromatic rings, carbonyls or thioketones, alkynes, and alkenes.
- P450 enzymes are responsible for many conversions related to these functional groups
Drug Design Considerations
- Drug design should consider drug metabolism to avoid unwanted interactions.
- Stabilizing functional groups can prevent enzymatic cleavage.
- Modifying functional groups can reduce drug susceptibility to specific enzymes.
- Example: Replacing a hydrogen atom with a fluorine atom can prevent undesirable reactions with certain drug molecules.
Reduction Reactions
- Drugs with carbonyl, azo, and nitrile groups can undergo reduction reactions by reductases.
Hydrolysis Reactions
- Drugs with ester or amide bonds can be hydrolyzed by esterases within the body.
Glucuronidation
- Involves attaching a glucuronic acid molecule to a drug molecule.
- UDPGA is the glucuronyl co-substrate involved in this process.
- Increases drug water solubility which facilitates excretion.
Sulfation
- Introduces a sulfate group to a drug molecule.
- The co-substrate involved is 3'-phosphoadenosine-5'-phosphosulfate (PAPS).
- Increases drug water solubility.
Glutathione Conjugation
- Attaches a glutathione molecule to a drug molecule.
- GSH (glutathione) is the primary substrate.
- Important for detoxifying reactive metabolites.
Acetylation
- Introduction of an acetyl group to a drug molecule.
- Catalyzed by N-acetyltransferases (NAT).
Amino Acid Conjugation
- Attaches an amino acid to a drug molecule.
- Often involves an activation step followed by reaction with an amino acid.
Methylation
- Introduces a methyl group to a drug molecule.
- Catalyzed by S-adenosylmethionine-methyltransferase (SAM).
Fatty Acid Conjugation
- Attaches a fatty acid molecule to a drug.
- Often increases the lipophilicity of the drug.
Cholesterol Conjugation
- Attaches a cholesterol molecule to a drug molecule.
- Further decreases water solubility.
CYP Enzyme Variability
- Genetic variations among individuals considerably affect the activity of CYP enzymes.
- Enzyme expression levels can vary; some individuals express higher amounts of certain CYP enzymes, impacting drug metabolism.
- Age, gender, diet, and certain drug exposures can influence CYP enzyme expression and activities, potentially modifying drug metabolism.
Factors Affecting Drug Biotransformation
- Enzyme induction or inhibition
- Age and gender
- Circadian rhythms
- Genetic variations.
Drug-Drug Interactions
- Induction or inhibition of enzymes
- Dosage adjustments
- Example involving rifampin and oral contraceptives; charcoal-broiled food and theophylline.
Herbal Remedies
- Certain components in some herbal remedies can induce P450 enzymes, impacting metabolism of other drugs.
P450 Subtypes
- CYP1A2, CYP2E1, CYP2C9, CYP2D6, and CYP3A4
- Different CYP enzymes are important, based on the substrates for these enzymes
Phase III Reactions (Drug Elimination)
- Transporter proteins are crucial in moving drug metabolites across cell membranes
- Lipid-soluble metabolites can cross membranes but water-soluble metabolites require specific transporter proteins
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Description
Test your knowledge on pharmacogenomics and biotransformation in this comprehensive quiz. Topics include gene polymorphisms, SNPs, enzyme functions, and their implications in drug metabolism. Perfect for students of genetics and pharmacology.
