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Questions and Answers
Which families of cytochrome P450 enzymes are primarily responsible for drug metabolism?
Which families of cytochrome P450 enzymes are primarily responsible for drug metabolism?
What is the main role of Uridine Diphosphate Glucuronosyl Transferases (UGTs) in drug metabolism?
What is the main role of Uridine Diphosphate Glucuronosyl Transferases (UGTs) in drug metabolism?
Which of the following states is true regarding glucuronides formed during the glucuronidation reactions?
Which of the following states is true regarding glucuronides formed during the glucuronidation reactions?
What role do 'perpetrator' drugs play in drug-drug interactions?
What role do 'perpetrator' drugs play in drug-drug interactions?
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Which process describes the conjugation of a drug with glucuronic acid?
Which process describes the conjugation of a drug with glucuronic acid?
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What is a significant aspect of drug metabolism that affects drug efficacy?
What is a significant aspect of drug metabolism that affects drug efficacy?
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Which of the following best describes 'genetic polymorphism' in the context of drug metabolism?
Which of the following best describes 'genetic polymorphism' in the context of drug metabolism?
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What type of interaction occurs when one drug reduces the metabolism of another drug?
What type of interaction occurs when one drug reduces the metabolism of another drug?
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What type of metabolic reactions are primarily involved in the Phase I metabolism of drugs?
What type of metabolic reactions are primarily involved in the Phase I metabolism of drugs?
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Which of the following is NOT a Phase II metabolic reaction?
Which of the following is NOT a Phase II metabolic reaction?
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What role do cytochrome P450 enzymes play in drug metabolism?
What role do cytochrome P450 enzymes play in drug metabolism?
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High doses of acetaminophen can lead to which of the following toxicological outcomes?
High doses of acetaminophen can lead to which of the following toxicological outcomes?
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What is the primary purpose of Phase II metabolic reactions?
What is the primary purpose of Phase II metabolic reactions?
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What metabolic fate do drug molecules predominantly follow after Phase I and Phase II metabolism?
What metabolic fate do drug molecules predominantly follow after Phase I and Phase II metabolism?
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Which of the following accurately describes a characteristic of metabolic activation?
Which of the following accurately describes a characteristic of metabolic activation?
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In the context of drug metabolism, what does the term 'hydrolysis' refer to?
In the context of drug metabolism, what does the term 'hydrolysis' refer to?
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What is the primary goal of drug metabolism in the human body?
What is the primary goal of drug metabolism in the human body?
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Which organ is primarily responsible for drug metabolism in the human body?
Which organ is primarily responsible for drug metabolism in the human body?
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What role do Cytochrome P-450 enzymes play in drug metabolism?
What role do Cytochrome P-450 enzymes play in drug metabolism?
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What is one consequence of the first-pass effect on drug metabolism?
What is one consequence of the first-pass effect on drug metabolism?
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What is the primary product of cyclobenzaprine metabolism?
What is the primary product of cyclobenzaprine metabolism?
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Which phase of drug metabolism typically involves conjugation reactions?
Which phase of drug metabolism typically involves conjugation reactions?
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What is the role of toxicological metabolic activation in drug metabolism?
What is the role of toxicological metabolic activation in drug metabolism?
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Which of the following cytochrome P-450 enzymes is least involved in the metabolism of cyclobenzaprine?
Which of the following cytochrome P-450 enzymes is least involved in the metabolism of cyclobenzaprine?
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Study Notes
Pharmacokinetics and Drug Metabolism
-
Drug Metabolism Overview:
- Part of elimination (metabolism and excretion)
- Chemical alteration of the drug by the human body
- Goal: Convert lipophilic drug molecules into polar species suitable for excretion
- Sites: Nearly every tissue has some metabolic capacity, but the major site is the liver. Other significant sites include the GI tract (including microbiome), kidneys, lungs, and skin.
- Drugs are metabolized by specialized enzymatic systems
Package Insert for AMRIX (Cyclobenzaprine)
- Metabolism and excretion: Extensively metabolized, primarily as glucuronides via the kidney.
- Cytochromes P-450 3A4, 1A2, and 2D6 mediate N-demethylation (an oxidative pathway)
- Elimination half-life: 32 hours (range 8-37 hours; n=18)
- Plasma clearance: 0.7 L/min following single-dose administration
The Journey of a Drug
- Drugs/compounds are metabolized in the liver for better elimination (first-pass effect)
- Some drugs undergo enterohepatic recirculation (e.g., chloramphenicol)
Pharmacological Consequences of Metabolism
- Activity lost (pharmacological deactivation): Metabolic transformation terminates pharmacological activity. Most drugs are deactivated by metabolism.
- Activity remains (active metabolites): Metabolic transformation does not result in activity loss; the metabolite activity may be stronger or weaker than the parent drug. Examples include phenytoin, buspirone, and 6-hydroxybuspirone.
Metabolic Activation
- Therapeutic: Inactive parent drugs are activated by metabolic transformation. Examples include enalapril (converted to enalaprilate) and tamoxifen (converted to 4-hydroxytamoxifen).
- Toxicological: Metabolic transformation converts drugs into toxic species (undesirable outcome). Example: acetaminophen at high doses can be activated into a toxic metabolite, leading to hepatic necrosis.
Metabolic Reactions
- Phase I: Oxidation (hydroxylation, deamination, dealkylation, sulfoxidation) or Reduction or Hydrolysis
- Phase II: Conjugation (glucuronic acid, sulfuric acid, glutathione, amino acid, acetylation, methylation)
Metabolic Fate of Drug Molecules: Summary
- Molecules can be eliminated unchanged by the kidneys
- Undergo phase I and phase II metabolic reactions in the liver
- Those conjugated are eliminated through the kidneys
Metabolism Complexity: Propranolol
- Propranolol has at least 11 phase I and 12 phase II metabolites.
Enzymes Involved in Drug Metabolism
- Cytochrome P450
- UDP-glucuronosyl transferase
- Epoxide hydrolase
- Glutathione S-transferase
- N-acetyltransferase
- Flavin-containing monooxygenase
- Prostaglandin synthase
- Quinone reductase
- Alcohol dehydrogenase
- Aldehyde and ketone dehydrogenase
- N-methyl and O-methyl transferase
- Sulfotransferase
- Monoamine oxidase
Cytochrome P450s
- Membrane-bound proteins located in the smooth endoplasmic reticulum (ER), most abundant in the liver
- Hemoproteins
- Monooxygenase reaction
Examples of Phase I Reactions: Oxidations
- Aromatic hydroxylation
- Aliphatic hydroxylation
- N-dealkylation
- N-oxidation
The Cytochrome P450 Superfamily
- Superfamily of enzymes with many isoforms to handle diverse chemical structures.
- Classified into families and subfamilies based on sequence homology.
- CYP2E1 is an example of a CYP isoform (family 2, subfamily E, first enzyme identified)
- Most involved in the metabolism of endogenous compounds (steroids, bile acids) and 15 are involved in drug metabolism (families 1, 2, and 3).
CYP P450 Family Tree
- Hierarchical structure showing the relationships between CYP isoforms.
Role of CYP Enzymes in Hepatic Drug Metabolism
- Relative hepatic content and percentages of drugs metabolized by each CYP enzyme
Glucuronosyl Transferases (UGTs)
- Uridine Diphosphate Glucuronosyl Transferases (UGTs)
- Located in the ER
- Catalyze the transfer of activated glucuronic acid onto a nucleophilic site on the drug molecule.
- Glucuronides are excreted into the bile or urine.
- Glucuronides are generally pharmacologically inactive.
Glucuronidation Reaction
- Reaction catalyzed by UGTs to add glucuronic acid to drug molecules.
Examples of Glucuronidation Reactions
- Examples of compounds that undergo glucuronidation (morphine, coumarin, and7-hydroxycoumarin).
Clinically Important Aspects of Drug Metabolism
- Induction
- Inhibition
- Genetic polymorphism
Metabolic Drug-Drug Interactions (DDIs)
- Drug-drug interaction: One drug alters the activity of another when both are administered together.
- Perpetrators: Drugs causing interactions, usually inhibitors or inducers of drug metabolism
- Victims: Drugs exhibiting side effects or rendered inactive by perpetrator drugs (drugs with only 1 or 2 significant elimination pathways)
Perpetrators and Victims in the Context of DDI
- Graphical representation showing how perpetrators as inhibitors or inducers can affect plasma concentrations of victim drugs, potentially causing beneficial or adverse effects.
St. John's Wort
- Herbal supplement that induces CYP3A4.
- This can reduce the bioavailability of drugs metabolized by CYP3A4.
Genetic Polymorphism
- Not all individuals metabolize drugs in the same manner.
- Loss-of-function variants decrease clearance and increase plasma concentrations.
- Gain-of-function variants increase clearance and decrease plasma concentration.
- Major polymorphic isoforms include CYP2D6, CYP2C9, and CYP2C19.
Classic Example: CYP2D6 Phenotypes
- Graphical distribution of sparteine metabolism phenotypes in a Caucasian population, showing extensive, intermediate, ultrarapid, and poor metabolizers.
Package Insert for Imipramine
- Reduced activity of the drug-metabolizing isozyme CYP2D6 in a subset of the Caucasian population leading to potentially higher plasma concentrations of imipramine.
Summary of Metabolic Reactions
- Summary of enzymes (i.e., GST, P450, esterases, amidases, quinone reductases) involved in metabolic reactions.
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Description
Explore the key concepts of pharmacokinetics and drug metabolism, including the processes of elimination, chemical alterations of drugs, and the primary roles of various organs like the liver and kidneys. This quiz delves into the specifics of drug metabolism for Cyclobenzaprine and other compounds, emphasizing enzymatic systems involved in these processes.
