ADME: Drug Absorption and Metabolism

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Questions and Answers

If a drug binds extensively to tissues, how is the drug volume in the blood affected?

  • The drug volume in the blood increases.
  • The drug volume initially increases, then decreases.
  • The drug volume in the blood decreases. (correct)
  • The drug volume in the blood remains unchanged.

Which of the following volumes is closest to the total body water in a 70kg man?

  • 12L
  • 3L
  • 42L (correct)
  • 27L

What is the formula for calculating the apparent volume of distribution (V)?

  • V = Amount of drug in body * Concentration of drug in body
  • V = Concentration of drug in body / Amount of drug in body
  • V = Amount of drug in body / Concentration of drug in body (correct)
  • V = Amount of drug in body - Concentration of drug in body

A drug is administered intravenously. Which of the following is part of the correct sequence of locations it may pass through?

<p>Blood -&gt; Kidney -&gt; Urine (C)</p> Signup and view all the answers

Why do protein drugs typically have apparent volumes of distribution close to plasma volume?

<p>Due to their large molecular size, limiting their ability to cross membrane barriers. (C)</p> Signup and view all the answers

Which of the following is a characteristic of passive facilitated diffusion?

<p>Does not require energy and results in equal concentration on both sides at equilibirum. (D)</p> Signup and view all the answers

What is a key difference between active transport and passive facilitated diffusion?

<p>Active transport requires energy to move substrates against a concentration gradient, while passive facilitated diffusion does not. (B)</p> Signup and view all the answers

What primarily characterizes systemic administration following extravascular drug administration?

<p>The unchanged drug moves from the administration site to the measurement site, typically plasma. (C)</p> Signup and view all the answers

What is a major factor that reduces the permeability of drugs across biological membranes?

<p>Low lipophilicity (LogP). (D)</p> Signup and view all the answers

Why is intestinal absorption not necessarily equivalent to systemic absorption?

<p>Intestinal absorption can lead to metabolism and biliary excretion, altering the drug before it reaches systemic circulation. (C)</p> Signup and view all the answers

How does lipophilicity affect a drug's ability to cross the blood-brain barrier?

<p>Increased lipophilicity increases blood-brain barrier permeability. (A)</p> Signup and view all the answers

The renal glomerulus is highly permeable to molecules up to 5000g/mol, what characteristic of the glomerulus allows this?

<p>The tissue contains fenestrations. (A)</p> Signup and view all the answers

After systemic absorption, how do drugs distribute throughout the body?

<p>Drugs are distributed via the systemic circulation to various tissues and organs in the body. (B)</p> Signup and view all the answers

Which two organs are principally involved in drug elimination from the body?

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

What characteristics of Vinblastine & Vincristine cause them to have low blood-brain barrier permeability even with moderately high lipophilicity?

<p>They are large molecules and substrates of efflux transporters. (A)</p> Signup and view all the answers

How does a drug's charge influence its movement across cell membranes?

<p>Charged molecules move slower across membranes. (D)</p> Signup and view all the answers

Which of the following statements best describes the ADME processes?

<p>ADME processes occur simultaneously, with the rates of each process affecting the final drug exposure profile. (B)</p> Signup and view all the answers

What does 'disposition' represent in the context of drug pharmacokinetics?

<p>The irreversible loss of drug from the site of measurement, which includes both elimination and distribution. (B)</p> Signup and view all the answers

What is the primary role of efflux transporters like MDR1 at the blood-brain barrier?

<p>To prevent the entry of toxins and drugs into the brain. (A)</p> Signup and view all the answers

What aspect of a drug is most directly related to its permeability across a biological membrane?

<p>The drug in solution (solvated): a chemical entity (B)</p> Signup and view all the answers

What characterizes passive transcellular drug transport?

<p>Movement of drug from one side of the cell to another across the phospholipid bilayer. (D)</p> Signup and view all the answers

Which factor primarily determines transport across the blood-brain barrier?

<p>Lipophilicity, charge, and molecular size of the substance. (D)</p> Signup and view all the answers

What does FG represent in the context of oral systemic bioavailability?

<p>The fraction of drug that reaches the portal vein, escaping destruction within the walls of the GIT. (A)</p> Signup and view all the answers

What is a key characteristic of drug transport through blood capillaries (excluding testes, placenta, and CNS)?

<p>It is independent of lipophilicity, charge, or molecular size (up to ~500g/mol). (A)</p> Signup and view all the answers

Which of the following best describes the 'first-pass effect'?

<p>The metabolism of a drug as it passes through the intestinal wall and liver, reducing the amount reaching systemic circulation. (D)</p> Signup and view all the answers

How can adsorption to substances like charcoal in the gastrointestinal tract affect drug absorption?

<p>It reduces drug absorption by holding the drug in the GIT. (C)</p> Signup and view all the answers

What is the primary consequence of metabolism during the passage of a drug across the intestinal wall and through the liver?

<p>Reduced amount of drug reaching systemic circulation. (B)</p> Signup and view all the answers

Which process exemplifies enzymatic 'first-pass metabolism'?

<p>Hydrolysis of Penicillin G in the stomach's acidic environment, resulting in inactive products. (C)</p> Signup and view all the answers

A drug is administered and its apparent volume of distribution is calculated to be 5L. If the administered dose was 10mg, what does this volume indicate?

<p>The drug is primarily distributed within the plasma volume. (D)</p> Signup and view all the answers

Which of the following statements accurately describes the relationship between the fraction unbound (fu) and protein binding?

<p>A higher f<sub>u</sub> indicates less protein binding. (A)</p> Signup and view all the answers

A drug's unbound fraction in plasma (fub) is known. Can this information be used to accurately predict its unbound fraction in tissues (fut)?

<p>No, f<sub>ut</sub> cannot be reliably predicted from f<sub>ub</sub>. (C)</p> Signup and view all the answers

Assuming $f_u$ is constant, what is its relevance regarding drug concentration changes?

<p>Changes in total drug concentration (C) correlate linearly with changes in unbound drug concentration ($C_u$). (A)</p> Signup and view all the answers

Which plasma protein, known for its high abundance, is most likely to bind to a wide variety of drugs?

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

Which statement best captures the binding characteristics of lipophilic amine drugs (basic drugs)?

<p>They exhibit selective affinity for α-1 acid glycoprotein. (D)</p> Signup and view all the answers

How does high affinity of acidic drugs for plasma albumin and low binding affinity for tissue proteins affect the volume of distribution (V)?

<p>It leads to a smaller V (V &lt; 1 l/kg). (D)</p> Signup and view all the answers

Regarding drug-lipoprotein association, which statement is most accurate?

<p>It is a relatively weak interaction with a modest restrictive influence on drug substrate. (B)</p> Signup and view all the answers

Which equation represents the relationship for unbound fraction?

<p>$f_{ub} = C_u / C_t$ (C)</p> Signup and view all the answers

Flashcards

Intracellular volume (Vc)

Volume of water inside cells, approximately 3L in a 70kg man.

Extracellular volume (VE)

Volume of fluid outside cells, about 12L, includes interstitial fluid.

Volume of distribution (V)

Relates drug amount in body to its concentration in plasma or blood.

Protein binding

Drugs may bind to plasma and tissue proteins, affecting their volume and action.

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Unbound fraction (fu)

Concentration of drug that is not bound to proteins, influencing drug activity.

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Drug in solution

A drug must be dissolved to cross cell membranes effectively.

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Passive Diffusion

Movement of substances down a concentration gradient without energy. Most common transport mechanism for drugs.

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Facilitated Diffusion

A type of passive transport using carrier proteins that do not require energy, highly specific to substrates.

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Active Transport

Transport against a concentration gradient using energy (ATP), allows for directional movement of substances.

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Size (Physiochemical factor)

Drug permeability decreases as molecular size increases; larger molecules are less likely to permeate gut membranes.

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Lipophilicity (LogP)

A measure of how well a drug partitions between octanol and water; higher lipophilicity means better membrane permeability.

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Charge effect on transport

Charged molecules move slower across membranes; drugs exist in ionized and unionized forms based on pH and pKa.

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Blood-Brain Barrier

A selective barrier with tight junctions that limits drug permeability; efflux transporters can remove drugs from the brain.

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Absorption

The process where a drug enters systemic circulation from the site of administration.

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Extravascular Administration

When a drug is administered outside the blood vessels, e.g., orally.

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Systemic Absorption

Achieved when drug concentration in blood becomes relatively uniform.

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Distribution

The process of a drug spreading throughout the body's tissues and organs post-absorption.

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Metabolism

The conversion of one chemical compound to another, primarily in the liver.

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Excretion

The irreversible removal of unchanged drugs from the body, primarily through kidneys.

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ADME Processes

The combined processes of Absorption, Distribution, Metabolism, and Excretion.

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Passive Transcellular Transport

Movement of drugs across cell membranes without energy, through the phospholipid bilayer.

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Membrane thickness

Thickness of biological membranes that affects drug transport.

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Transporters

Proteins that facilitate movement of substances across membranes.

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Oral systemic bioavailability (F)

Fraction of an orally administered drug reaching systemic circulation.

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First-Pass Metabolism

Process where drugs are metabolized before reaching systemic circulation.

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F_F, F_G, F_H

Fractions representing absorption stages in bioavailability: intestinal, portal vein, liver.

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Efflux Transporters

Proteins that reduce drug absorption by pumping it out of the cells.

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Apparent Volume of Distribution

Hypothetical volume that a drug would occupy in the body.

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Biological Membrane Permeability

Ability of substances to cross cell membranes influenced by properties.

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Differing affinity

Relationship of drug concentrations free and bound in tissues and plasma.

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Free/unbound drug (Fu)

Drug that is not bound to proteins, available for action and elimination.

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Equilibrium in drug distribution

Balance between unbound and bound drugs in plasma and tissues.

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Albumin

Most abundant plasma protein that binds many drugs, especially acidic ones.

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fu range

Values between 0-1 indicating the degree of protein binding of a drug.

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Impact of fu on PK parameters

Changes in fu change drug volume and clearance, affecting overall disposition.

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Acidic drug binding

Acidic drugs bind mainly to albumin, affecting their distribution volume.

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Basic drug binding

Basic drugs prefer binding to albumin and lipoproteins, often with lower affinity for tissues.

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Study Notes

Drug Absorption, Distribution, Metabolism, and Excretion (ADME)

  • Absorption is the process of a drug moving from the site of administration to the bloodstream.
  • Extravascular administration involves systemic absorption where the drug moves from the site of administration to the measurement site (typically blood plasma).
  • Oral absorption is an example of extravascular administration.
  • Intestinal absorption may not equal systemic absorption.
  • Distribution is the process where the drug moves throughout the body's tissues and organs via the systemic circulation.
  • Drug distribution rate and extent may differ between tissues.
  • Metabolism involves the body chemically changing a drug into other forms, often for easier excretion.
  • The liver and kidneys are the primary sites for metabolism and excretion.
  • Metabolism is an irreversible loss of a drug from measurement sites, meaning the original drug form is not present.
  • Excretion refers to the removal of drugs and their metabolites from the body.

Factors Affecting Drug Movement Across Membranes

  • Drug movement across membranes is important for absorption and distribution.
  • Passive diffusion is the most common mechanism, where drugs move from an area of high concentration to low concentration.
  • Passive diffusion depends on physiochemical properties like size, lipophilicity, and charge of the drug. Membrane thickness and transporter availability also influence drug movement.
  • Carrier-mediated transport uses proteins to facilitate drug movement.
  • Active transport requires energy to move drugs against their concentration gradient.

Factors Affecting Bioavailability

  • Oral bioavailability is the fraction of an administered drug that reaches the systemic circulation intact after oral administration, which is described as the first primary PK parameter.
  • Drugs are commonly administered orally.
  • Factors affecting bioavailability include:
    • First-pass metabolism, influencing drug loss in the liver.
    • Enzymatic or non-enzymatic degradation in the gut.
    • Efflux transporters that remove drug from the gut.
    • Extent of drug loss in the gut.

Apparent Volume of Distribution

  • This describes the theoretical volume of fluid in which a drug appears to be distributed in the body.
  • It is calculated from the relationship of drug amount and concentration in the body to its concentration in the plasma.
  • Clinical applications of apparent volume of distribution include determining the distribution characteristics of a drug.
  • It helps understand where the drug concentrates in the body (blood, tissues).

Drug-Protein Binding Interactions

  • Many drugs bind to proteins, primarily albumin.
  • Bound drug is pharmacologically inactive because it cannot reach its target.
  • The unbound fraction (free drug) is the active form of the drug.
  • The unbound fraction affects volume of distribution and clearance.
  • Changes in protein binding can significantly affect drug action.

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