Drug Metabolism: ADME Basics
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Questions and Answers

What percentage of drugs in clinical usage today are oxidised by CYP3A4?

  • 30%
  • 50% (correct)
  • 70%
  • 90%

    • What is the primary factor that influences drug formulation when drugs cross biological membranes?

  • Route of administration (correct)
  • Lipid solubility of the drug
  • pH of the biological membrane
  • Tissue effects of the drug

    • What is the base unit for glucuronidation in Phase II metabolism?

  • Fructose-1-phosphate
  • Glucose-1-phosphate (correct)
  • Galactose-1-phosphate
  • Glucose-6-phosphate

    • Why are basic or acidic groups useful in drug design?

    <p>They improve drug absorption by facilitating crossing of biological membranes</p> Signup and view all the answers

    What is the effect of depleting the GSH pool in glutathione conjugation?

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

    What is the primary application of the theory of volume of distribution (VD)?

    <p>Identifying the best therapy for a given condition</p> Signup and view all the answers

    What is the effect of metabolism on drugs?

    <p>Can either activate or inactivate drugs</p> Signup and view all the answers

    What is the primary focus of the learning outcome 'Explain how drugs cross the biological membrane by different routes and how this influences drug formulation'?

    <p>The mechanisms of drug transport across biological membranes</p> Signup and view all the answers

    What determines the net effect of renal excretion?

    <p>The balance of glomerular filtration, tubular secretion, and tubular re-absorption</p> Signup and view all the answers

    What is the primary benefit of applying knowledge of drug design modification to improve penetration of target tissue?

    <p>Optimized therapy for a given condition</p> Signup and view all the answers

    What is the effect of multiple metabolic pathways on a single molecule?

    <p>Can either activate or inactivate the molecule</p> Signup and view all the answers

    What is the primary reason why ADME is important in drug development?

    <p>It informs the development of effective and safe drug therapies</p> Signup and view all the answers

    What is the primary factor that determines the glomerular filtration rate?

    <p>Hydrostatic pressure gradient</p> Signup and view all the answers

    What is the significance of the fraction of unbound drug in plasma in glomerular filtration?

    <p>It changes the rate of renal elimination</p> Signup and view all the answers

    What is the primary route of excretion for drugs that are not excreted via the kidney?

    <p>Bile and then intestine</p> Signup and view all the answers

    What is the consequence of changes in the amount of plasma protein on glomerular filtration?

    <p>It changes the rate of renal elimination</p> Signup and view all the answers

    What is the result of displacement from plasma protein by other drugs?

    <p>Changes in the fraction of unbound drug in plasma</p> Signup and view all the answers

    What is the characteristic of the hepatic sinusoids that enables first-pass metabolism?

    <p>Nutrient-rich environment</p> Signup and view all the answers

    What is the primary function of the hepatic vein in the context of drug metabolism?

    <p>To receive blood from the portal vein</p> Signup and view all the answers

    What type of transport is involved in liver excretion, as well as kidney route?

    <p>Transporter mediated</p> Signup and view all the answers

    What is the term for the process by which a drug is reabsorbed into the bloodstream after being excreted into the bile?

    <p>Enterohepatic circulation</p> Signup and view all the answers

    Which of the following references is NOT a primary source for the topic of drug metabolism?

    <p>Allocati et al.(2018) Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases.</p> Signup and view all the answers

    What is the term for the process by which the liver metabolizes a drug before it reaches the systemic circulation?

    <p>First-pass effect</p> Signup and view all the answers

    Which of the following is a type of enzyme involved in drug metabolism?

    <p>Glutathione S-transferases</p> Signup and view all the answers

    What is the primary mechanism by which P-glycoprotein confers multidrug resistance in tumors?

    <p>By actively effluxing anticancer drugs out of tumor cells</p> Signup and view all the answers

    What is the primary application of nanomedical solutions in the context of multidrug resistance?

    <p>Targeted delivery of anticancer drugs to tumor cells</p> Signup and view all the answers

    What is the primary role of CYP3A4 enzymes in the context of drug metabolism?

    <p>Phase I metabolism of xenobiotics</p> Signup and view all the answers

    What is the primary consequence of multidrug resistance in cancer therapy?

    <p>Decreased efficacy of chemotherapy</p> Signup and view all the answers

    What is the primary factor contributing to the development of multidrug resistance in cancer cells?

    <p>Overexpression of P-glycoprotein</p> Signup and view all the answers

    Plasma binding protein increases pharmacological action of a drug

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

    Increased volume of distribution indicates poor distribution of a drug throughout the body

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

    The primary role of albumin is to maintain colloidal osmotic pressure of blood

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

    Metabolism of a drug always leads to its activation

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

    Glomerular filtration rate is the primary factor that determines the rate of excretion of a drug

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

    Displacement of other drugs from plasma protein can increase their pharmacological action

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

    Rifampicin is a substrate of CYP3A4.

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

    Glucuronidation requires inorganic sulphate.

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

    Glutathione conjugation is a high energy conjugate reaction.

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

    The liver is a minor route of excretion.

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

    Tubular re-absorption is a passive process.

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

    GST conjugates can be used as a marker of efficacy.

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

    Dr. Sarah Bailey's consultation hours are on Wednesdays from 14.00 - 15.00.

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

    The theory of volume of distribution (VD) is used to identify the best therapy.

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

    Basic or acidic groups are not useful for improving drug absorption.

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

    The primary focus of the learning outcome is on the excretion of drugs.

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

    ADME is not important in drug development.

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

    Lipid solubility does not affect drug absorption or efficacy.

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

    Glomerular filtration is a dependent process.

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

    Large molecules (Mr >300) are often eliminated via the kidney.

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

    Changes in the fraction of unbound drug can affect the rate of liver elimination.

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

    Expression levels of drug transporters can change rapidly due to genetic mutations.

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

    The hepatic sinusoids are responsible for first-pass metabolism due to their characteristic of being nutrient-poor.

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

    Liver excretion is a type of active transport.

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

    Enterohepatic recirculation is a process where the liver excretes the drug and it gets reabsorbed into the bloodstream.

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

    The hepatic artery is responsible for carrying oxygenated blood to the liver.

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

    Glutathione S-transferases are involved in antioxidant defenses and xenobiotic metabolism.

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

    The Erythromycin Breath Test is used to predict the volume of distribution of a drug.

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

    P-glycoprotein is involved in the efflux of drugs from the liver.

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

    The portal vein carries deoxygenated blood from the liver to the heart.

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

    Study Notes

    CYP3A4 - Phase I Enzyme

    • CYP3A4 is the most abundant P450 in human liver, responsible for oxidizing >50% of drugs in clinical usage today
    • It has a very wide substrate specificity
    • Rifampicin and Metyrapone are examples of inducers of CYP3A4

    Phase II Metabolism

    • Phase II metabolism involves the addition of conjugates to increase hydrophilicity, resulting in a more polar metabolite that can be easily excreted
    • Glucuronic acid, sulphate, amino acids, glutathione, and acetylation are common conjugates used in Phase II metabolism
    • Multiple different enzymes are involved in Phase II metabolism, and these enzymes are inducible
    • The goal of Phase II metabolism is to produce a metabolite that is polar enough to be excreted via urine or faeces

    Types of Phase II Metabolism

    Glucuronidation

    • Glucuronidation is a high-energy conjugate reaction that uses glucose-1-phosphate as a base unit
    • It is a ubiquitous and highly expressed reaction in most species, except for cats
    • Glucuronidation is important in enterohepatic recirculation

    Sulphation

    • Sulphation has a similar substrate profile to glucuronidation
    • It is a high-energy conjugate reaction that may be limited by inorganic sulphate availability
    • Sulphation has a large variability in species and tissue expression

    Glutathione Conjugation

    • Glutathione conjugation involves the tripeptide Glu-Gly-Cys (GSH)
    • It is a low-energy conjugate reaction that is specific for halides and epoxides
    • GSH is ubiquitous and has a good conjugate pool, with both cytosolic and membrane-bound variants
    • Depletion of GSH pool can lead to toxicity, and GST conjugates may be a marker of toxicity

    Multiple Possibilities

    • Metabolism can occur at multiple sites within one molecule
    • Metabolism can activate or deactivate drugs, and the balance determines the outcome
    • Cyclophosphamide is an example of a drug that is activated in the liver, resulting in no adverse effects in the GIT

    Excretion

    • Excretion is the final clearance of drugs from the body
    • It is also the final chance to keep drugs in the body
    • Metabolism, kidney, liver, and GI tract are the major routes of excretion
    • Lungs, sweat, lacrimal fluid, and milk are minor routes of excretion

    Renal Excretion

    • Renal excretion is the net effect of glomerular filtration, tubular secretion, and tubular re-absorption
    • These processes are both passive and active
    • Multiple factors affect the rate of elimination, including kidney integrity, molecule size, urine flow, urine pH, and other compounds being excreted

    Glomerular Filtration

    • Glomerular filtration is a passive process dependent on hydrostatic pressure gradient
    • It has a size cut-off, allowing small molecules (most drugs) to pass through while removing plasma proteins
    • Filtration is dependent on the free drug in plasma, and changes in the fraction of unbound drug may change the rate of renal elimination

    Liver Excretion

    • Liver excretion is generally the route for drugs not excreted via the kidney
    • Large molecules (Mr >300) are often excreted via the liver, and may involve glucuronide conjugates
    • Liver excretion can be transporter-mediated, and may involve enterohepatic recirculation

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    Learn about the basics of drug metabolism, including routes of administration, crossing biological membranes, and influencing factors. Understand the pros and cons of different routes and how they affect drug metabolism.

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