Drug Metabolism Phase 1 Quiz
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Questions and Answers

Which of the following is NOT a phase 1 reaction involved in drug metabolism?

  • Reduction
  • Oxidation
  • Conjugation (correct)
  • Hydrolysis

    • Phase 1 reactions typically increase the lipid solubility of drugs, making them easier to eliminate from the body.

    False (B)

    What is the primary role of phase 1 reactions in drug metabolism?

    To introduce functional groups to the drug molecule, making it more reactive and preparing it for phase 2 reactions.

    The liver is a key organ for ______ reactions, which are the first step in drug metabolism.

    <p>phase 1</p> Signup and view all the answers

    Match the following terms with their descriptions:

    <p>Xenobiotics = Foreign chemicals that are not naturally produced by the body Chirality = The property of a molecule having non-superimposable mirror images Microsomal enzymes = Enzymes found in the smooth endoplasmic reticulum, responsible for drug metabolism Functionalisation = The process of introducing reactive groups to a molecule during phase 1 reactions</p> Signup and view all the answers

    Which of these drugs is NOT an inducer of microsomal enzymes?

    <p>aspirin (A)</p> Signup and view all the answers

    Enzyme induction always leads to increased drug toxicity and carcinogenicity.

    <p>False (B)</p> Signup and view all the answers

    What is the name of the receptor that is activated by polycyclic aromatic hydrocarbons and promotes transcription of genes inducing CYP1A1?

    <p>aryl hydrocarbon receptor (AHR)</p> Signup and view all the answers

    The ______ receptor and the ______ receptor are considered more important than the AHR in clinical drug-drug interactions.

    <p>Constitutive androsterone receptor (CAR)</p> Signup and view all the answers

    Match the following drugs with their respective mechanisms of action regarding microsomal enzyme induction:

    <p>Rifampicin = Induces CYP3A4 and other enzymes Ethanol = Stabilizes P450 protein and mRNA Carbamazepine = Induces CYP3A4 and other enzymes Phenobarbital = Induces glucuronyl transferase</p> Signup and view all the answers

    Pre-systemic metabolism refers to the breakdown of drugs before they reach the systemic circulation.

    <p>True (A)</p> Signup and view all the answers

    Which of the following factors can influence intestinal blood flow?

    <p>All of the above (D)</p> Signup and view all the answers

    What is the term used to describe drugs that are pharmacologically active only after metabolism?

    <p>Pro-drugs</p> Signup and view all the answers

    Azathioprine is metabolized to ______ which is pharmacologically active.

    <p>mercaptopurine</p> Signup and view all the answers

    Variations in hepatic blood flow do NOT significantly impact pre-systemic metabolism.

    <p>False (B)</p> Signup and view all the answers

    Which P450 enzymes mediate the majority of drug metabolism?

    <p>CYPs 1A2, 3A4, 2D6, 2C9, and 2C19 (D)</p> Signup and view all the answers

    P450 enzymes are only involved in drug oxidation reactions.

    <p>False (B)</p> Signup and view all the answers

    Name one environmental inhibitor of P450 enzymes.

    <p>Grapefruit juice</p> Signup and view all the answers

    The CYP enzyme family is classified based on __________ similarities.

    <p>amino acid</p> Signup and view all the answers

    What is produced when a drug substrate is hydroxylated?

    <p>A hydroxylated product (C)</p> Signup and view all the answers

    Match the following components required for drug oxidation by the P450 system:

    <p>Drug substrate ('DH') = The molecule undergoing transformation NADPH = Electron donor P450 enzyme = Biocatalyst for the reaction NADPH-P450 reductase = Flavoprotein facilitating electron transfer</p> Signup and view all the answers

    All human CYPs are involved in drug metabolism.

    <p>False (B)</p> Signup and view all the answers

    What is the effect of 3-methylcolanthrene on P450 enzyme activity?

    <p>It acts as an inducing agent.</p> Signup and view all the answers

    Which drug is hydrolyzed to yield a metabolite that retains anti-inflammatory effects but lacks antiplatelet activity?

    <p>Aspirin (A)</p> Signup and view all the answers

    Metabolites of a drug can be responsible for drug toxicity.

    <p>True (A)</p> Signup and view all the answers

    What is the effect of enzyme induction on drug metabolism?

    <p>It increases the metabolism of certain drugs, reducing their effectiveness.</p> Signup and view all the answers

    Chronic alcohol consumption can increase the risk of serious hepatic injury following paracetamol overdose by inducing ______ enzymes.

    <p>CYP</p> Signup and view all the answers

    Match the following drugs with their interactions:

    <p>Rifampicin = Reduces warfarin's anticoagulant effect Protease inhibitors = Potent CYP inhibitors Metronidazole = Example of enzyme inhibitor Carbamazepine = Requires gradual dose increase to avoid toxicity</p> Signup and view all the answers

    Which of the following is a consequence of enzyme inhibition?

    <p>Decreased action of drugs metabolized by the enzyme (D)</p> Signup and view all the answers

    Enzyme induction has a rapid onset and recovery.

    <p>False (B)</p> Signup and view all the answers

    What agent is used to treat poisoning from methanol and ethylene glycol?

    <p>Ethanol</p> Signup and view all the answers

    What is one primary reason for predicting drug interactions?

    <p>To personalize treatment based on phenotype (A)</p> Signup and view all the answers

    All drug reactions involve hepatic enzymes.

    <p>False (B)</p> Signup and view all the answers

    What enzyme is responsible for oxidizing warfarin?

    <p>CYP2C9</p> Signup and view all the answers

    Ethanol is metabolised by both CYP2E1 and ________ in the cytoplasm.

    <p>alcohol dehydrogenase</p> Signup and view all the answers

    Match the following enzyme reactions with their corresponding drug interactions:

    <p>Xanthine oxidase = Inactivates 6-mercaptopurine Monoamide oxidase = Inactivates biologically active amines CYP2A6 = Catalyzes reduction of warfarin UDP-glucuronyl transferase = Catalyzes glucuronidation reactions</p> Signup and view all the answers

    Which of the following statements is true regarding hydrolytic reactions?

    <p>They can occur in plasma and many other tissues. (C)</p> Signup and view all the answers

    Reduction is more common than oxidation in phase 1 metabolism.

    <p>False (B)</p> Signup and view all the answers

    What is formed from the glucuronidation of substrates?

    <p>Amide, ester, or thiol bonds</p> Signup and view all the answers

    Phase 2 reactions tend to produce ________ products, with exceptions like the active sulphate metabolite of minoxidil.

    <p>inactive</p> Signup and view all the answers

    Which of the following drugs is mentioned as having stereoisomers that can interact with metabolism?

    <p>Warfarin (D)</p> Signup and view all the answers

    Study Notes

    Drug Metabolism

    • Animals have evolved intricate systems to detoxify foreign chemicals (xenobiotics), including carcinogens and toxins from poisonous plants.
    • Drugs are a specialized category of xenobiotics, often exhibiting chirality, meaning they exist as different stereoisomers.
    • Drug chirality influences metabolism.
    • Drug metabolism involves two types of reactions, phase 1 and phase 2, typically occurring sequentially.
    • Phase 1 and phase 2 reactions decrease the lipid solubility of the compounds, enhancing renal elimination of xenobiotics.

    Phase 1 Reactions

    • Phase 1 reactions (e.g., oxidation, reduction, hydrolysis) are categorized as catabolic.
    • Products of phase 1 reactions are often more chemically reactive and potentially more toxic or carcinogenic than the original drug.
    • Phase 1 reactions introduce reactive groups (e.g., hydroxyl) into the molecule, a process termed functionalization.
    • These reactive groups act as attachment points for phase 2 conjugation systems (e.g., glucuronide attachment).
    • Phase 1 reactions commonly precede phase 2 reactions due to the functionalization requirement.
    • The liver is a crucial organ for phase 1 reactions.
    • Hepatic drug-metabolizing enzymes, including CYP enzymes, are localized in the smooth endoplasmic reticulum (microsomal fraction).
    • Drugs must cross the plasma membrane to reach these metabolizing enzymes.
    • Polar molecules cross the plasma membrane less readily than non-polar molecules, unless specific mechanisms exist.

    Cytochrome P450s

    • CYP enzymes, haem proteins, are part of a large superfamily of related but distinct enzymes involved in numerous reactions.
    • Each enzyme is designated as CYP followed by specific numbers and a letter.
    • CYP enzymes vary in amino acid sequences, sensitivity to inhibitors and inducing agents, and reaction specificity.
    • P450 enzymes possess distinct but overlapping substrate specificities.
    • Classification of P450 enzymes is based on amino acid sequence similarities determined through purification and cloning.
    • CYP enzyme family 1-3 mediate around 70-80% of all phase 1 dependent metabolism of clinically used small molecule drugs.
    • 12 CYP enzymes account for approximately 93% of drug metabolism in 1839 known drug metabolising reactions.

    CYP Reaction Mechanism

    • The CYP mechanism requires several components: the drug substrate (DH), P450 enzyme, molecular oxygen, NADPH, and NADPH-P450 reductase (a flavoprotein).
    • The mechanism is a cyclical process.
    • The reaction outcome is the addition of one oxygen atom from molecular oxygen to the drug, resulting in hydroxylation to form DOH.
    • The other oxygen atom forms water.
    • Hydroxylation introduces a hydroxyl group into an organic molecule.
    • Reduced forms of CYP bind carbon monoxide, resulting in distinct absorbance peaks.
    • Drug metabolism can be influenced by factors such as the existence of inducing agents.

    P450 Biological Variation

    • Species differences influence the choice of species for toxicity and carcinogenicity testing during drug development.
    • Variations in P450 enzymes are significant in humans, impacting drug therapies.
    • Variations arise from genetic polymorphisms (alterations in DNA sequences) and environmental factors.
    • Examples of environmental factors include grapefruit juice (inhibitor), brussel sprouts, and cigarette smoke (inducers), and St. John's Wort (induces CYP450 isoenzymes).
    • Drug interactions often occur as a result of one drug influencing another's metabolism.
    • Predicting drug interactions and individualizing treatment depend on understanding an individual's phenotype.
    • Drugs' effects may not be limited to hepatic enzymes, with plasma, lung, and gut enzymes also involved.

    Hydrolytic Reactions

    • Hydrolytic reactions are chemical reactions where water functions as a nucleophile to break a chemical bond.
    • These reactions occur in plasma and other tissues.
    • Both ester and amide bonds are susceptible to hydrolytic cleavage.
    • Esters are generally less readily cleaved compared to other bonds.

    Reduction Reactions

    • Reduction reactions are less common than oxidation reactions in phase 1 metabolism.
    • An example of reduction is the conversion of keto groups (in warfarin) to hydroxyl groups.
    • CYP2A6 catalyzes this reduction, producing inactive alcohols.
    • Warfarin is also oxidized by CYP2C9, resulting in the formation of inactive hydroxylated metabolites.
    • The primary route of warfarin inactivation is through oxidation by CYP2C9.

    Phase 2 Reactions

    • Phase 2 reactions are synthetic (anabolic), involving a substituent group conjugation.
    • These reactions often produce inactive products.
    • Exceptions include active sulphate metabolites of minoxidil.
    • Phase 2 reactions primarily occur in the liver.
    • Phase 1 products (e.g., with hydroxyl, thiol, or amino groups) are prone to conjugation.
    • Common phase 2 conjugates include glucuronyl, sulphate, methyl, and acetyl groups.
    • Examples:
    • Glutathione conjugates drugs or phase 1 metabolites.
    • Glucuronidation involves transferring glucuronic acid to the substrate.
    • UDP-glucuronyl transferase catalyzes these reactions and has broad substrate specificity.
    • Acetylation (using acetyl-CoA) and methylation (using SAM) are additional types of Phase 2 reactions.
    • Although primarily located in the liver, these reactions also occur in other tissues such as lungs and kidneys.

    Stereoselectivity

    • Many clinically important drugs, such as sotalol, warfarin, and cyclophosphamide, are mixtures of stereoisomers.
    • Stereoisomers can display different pharmacological effects and metabolic pathways.
    • Clinically important drug interactions often involve stereospecific inhibition of one drug's metabolism by another.
    • Drug toxicity is frequently linked to a single stereoisomer, not necessarily the active form.
    • Regulatory authorities recommend, wherever practical, drugs consisting of pure active isomers to reduce complications.
    • The practicality of using single isomers is debated, especially when dealing with well-established racemates.
    • Enzymatic interconversion of stereoisomers can detract from the benefits of designing drugs as single isomers.

    Inhibition of P450s

    • P450 inhibitors exhibit selectivity for different isoforms.
    • Inhibition mechanisms vary.
    • Some inhibitors compete for the active site but are not substrates.
    • Non-competitive inhibitors form tight complexes with iron, causing reversible enzyme inhibition.
    • Mechanism-based inhibitors bind covalently to the enzyme, leading to self-destruction (suicide inhibition).
    • Examples include ketoconazole, and gestodene.

    Induction of Microsomal Enzymes

    • Enzyme induction, especially with repeated administration, increases the activity of microsomal oxidase and conjugating systems.
    • Induction is a result of increased synthesis and/or decreased breakdown of microsomal drug metabolizing enzymes, such as CYP enzymes.
    • Induction can increase drug toxicity and carcinogenicity.
    • Inducing agents can be used therapeutically (e.g., phenobarbital in premature babies with potential for kernicterus).
    • Examples of inducing agents include specific chemicals.
    • Some agents influence drug interactions involving transcription factors, like CAR and PXR.

    Pre-Systemic Metabolism

    • After oral administration some drugs undergo presystemic metabolism in the liver or gut wall.
    • Presystemic metabolism reduces the bioavailability of the drug.
    • Challenges associated with pre-systemic metabolism include needing higher oral doses, variability among individuals, and potential interactions with other drugs affecting the liver or intestine.

    Pharmacologically Active Drug Metabolites

    • Some drugs are not active until after metabolism (pro-drugs).
    • Examples include azathioprine and enalapril.
    • Drug metabolism can change how a drug acts.
    • Metabolites of drugs can sometimes have similar effects or have different effects than the original drug (e.g., aspirin produces salicylic acid which has anti-inflammatory effects).
    • Metabolites can cause toxicity (e.g., methanol and ethylene glycol).

    Interactions Caused by Enzyme Induction

    • Enzyme induction is a major cause of drug interactions.
    • Enzyme induction can cause variability in drug response.
    • Induction may be slower and more complicated.
    • Interactions can have adverse effects.
    • Pharmacokinetics of some interactions can improve or decrease tolerance/effectiveness.

    Interactions Caused by Enzyme Inhibition

    • Enzyme inhibition, especially of CYP enzymes, can affect drug metabolism and lead to increased concentrations of other drugs.
    • Protease inhibitors from HIV treatment are potent CYP inhibitors, impacting combination therapy.
    • Examples of enzyme inhibitors include metronidazole, omeprazole, and amiodarone.
    • These can inhibit certain drugs' metabolism.
    • Some drugs can inhibit metabolic pathways resulting in their own increased effectiveness.
    • Co-prescribing drugs with inhibition potential needs careful assessment to avoid unwanted side effects.

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    Drug Metabolism (PED2001) PDF

    Description

    Test your knowledge on phase 1 reactions involved in drug metabolism. This quiz covers key concepts, including enzyme inducers, liver functions, and specific receptors related to drug metabolism. Assess your understanding of how these reactions work and their implications in pharmacology.

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