Toxicokinetic exam preparation

Knowledge

1. What is Toxicokinetics and Toxicodynamics?

Toxicokinetics describes the movement of (potentially toxic) molecules in the organism to the target. It refers to “What the body does to the chemical”.

Toxicodynamics describes the relation between number of molecules at the target site and the toxic effect.

It refers to “What the chemical does to the body”

2. ADME

• Absorption: Entrance of a substance into the body
• Distribution: Movement of a substance from the site of entrance to other tissues and organs
• Metabolism: Transformation of a parent substance to other compounds (metabolites)
• Excretion: Exit of the substance from the body

Affecting factors:

1. The chemical: dose, size, solubility, lipophilicity, ionisation, reactivity, etc
2. The organism: species, body composition, expression of biotransformation enzymes, etc

3. Transport mechanisms

• Diffusion – random movement of molecules
• Facilitated diffusion - Transport with a concentration gradient (high-to-low)
• Active transport - Transport against a concentration gradient
• Endocytosis - Uptake of small particles and liquids
• Bulk flow - movement of substances at equal rates or as a single body (e.g. blood flow)

4. Toxicokinetic models

• Simple descriptive: Non-compartment model
  • No assumption, simple, cost-efficient
  • No extrapolation, do not reflect personal difference
• Descriptive: Compartment model
• Predictive: PBTK model
  • Extrapolation tool

Previous exam 2023

1. Name four reasons why in vitro systems are useful for metabolism studies in drug discovery.

In vitro systems are useful for metabolism studies in drug discovery because they:

1. Allow controlled environments to study specific enzymes and pathways.
2. Enable rapid screening of multiple compounds for metabolic stability.
3. Reduce the need for animal studies, aligning with ethical considerations.
4. Provide early insights into potential drug-drug interactions.

Answered by ChatGPT

2. State four important questions asked in chemical risk assessment that relates to toxicokinetics.

In chemical risk assessment, important questions related to toxicokinetics include:

1. How is the chemical absorbed, distributed, metabolized, and excreted (ADME) in the body?
2. What are the exposure levels and durations that lead to toxic effects?
3. How does the chemical bioaccumulate in tissues or organs over time?
4. Are there differences in toxicokinetics across populations (e.g., age, gender, health status)?

Answered by ChatGPT

3. Pick three toxicokinetic parameters, a) describe their relevance for an adverse outcome upon chemical exposure, and b) give example of one potential biological factor that may influence each of these parameters (one per parameter).

Here are three toxicokinetic parameters, their relevance, and a biological factor that influences each:

1. Absorption 
   a) Relevance: Controls chemical entry into the bloodstream, affecting toxicity.  
   b) Factor: Gastrointestinal pH—alters absorption rates for oral chemicals.

2. Metabolism 
   a) Relevance: Converts chemicals to either detoxified or more toxic forms.  
   b) Factor: Liver enzyme activity—varies metabolism speed, impacting toxicity.

3. Excretion 
   a) Relevance: Influences how long chemicals remain in the body and exert effects.  
   b) Factor: Kidney function—slower excretion increases chemical retention and risk.

Answered by ChatGPT

4. Describe two major exposure routes and what type of substances that humans are exposed to via these routes.

• Airways: gases, vapors, aerosols, respirable particles, pharmaceutical drugs
• Skin: chemcial spills, detergents, chemcials in cosmetics
• GI tract: contaminants in foods and beverages, pharmaceutical drugs, non-respirable particles

From slides

5. Describe and compare the transport mechanisms “diffusion” and “active transport”, and briefly describe how they relate to the chemical properties of the compound being transported.

Diffusion is passive, moving molecules from high to low concentration without energy, favoring small, non-polar compounds.  
Active transport requires energy to move molecules against a gradient, often for larger, polar compounds.

Comparison:  
- Energy: Diffusion is passive; active transport uses energy.
- Direction: Diffusion follows the gradient; active transport goes against it.
- Compound types: Diffusion suits small, non-polar compounds, while active transport handles larger, polar ones.

Answered by ChatGPT

6. At oral exposure of for example a pharmaceutical drug, state four key parameters (chemical and/or biological) affecting the absorption.

In oral exposure to a pharmaceutical drug, four key parameters affecting absorption are:

1. Solubility of the drug in gastrointestinal fluids.
2. Permeability of the drug across the intestinal membrane.
3. Gastrointestinal pH, influencing drug ionization and absorption.
4. Presence of food, which can delay or enhance absorption.

Answered by ChatGPT

7. What does the “free drug principle” mean?

According to the “Free drug principle”, it is only free drug that crosses membranes and can interact with the biological target.

From slides

8. A compounds LogKow is important for its toxicokinetic characteristics. A)What is logKow a measurement of? b) What is it often used to estimate? And c) where in the body is a compound with high LogKow likely to be distributed to?

A) The logarithmic measurement of a compound’s
distribution between octanol and water.
b) logKow can be used to estimate the distribution of organic compounds between water and lipids
c) A compound with a high LogKow is likely to be distributed to lipid-rich tissues in the body, such as adipose tissue and the central nervous system.

A) and b) are from slides, c) from ChatGPT

9. Which of these toxicokinetic models are predictive? Select one or more alternatives: (multiple choice)

• a) Non-compartmental model
• b) Compartmental model
• c) PBPK model
• d) none of the above models

10. Briefly describe what the following toxicokinetic variables mean, a) target dose, b) surrogate dose, c) half-life (t1/2), and d) total clearance.

a) Target dose: The amount of a chemical that reaches the site of action in the body to produce an effect.

b) Surrogate dose: A measurable dose (e.g., in blood or urine) that serves as an indicator of the actual exposure or target dose.

c) Half-life (t1/2): The time it takes for the concentration of a chemical in the body to decrease by half.

d) Total clearance: The rate at which a chemical is removed from the body via all elimination routes (e.g., metabolism, excretion).

11. Briefly describe a) what a PBPK model is, b) what type of parameters PBPK models are based on, and c) what is the process for PBPK model development.

a) PBPK model(physiologically based pharmacokinetic model) mathematically describes and predicts the disposition of chemicals using key physiologic parameters and mechanistic data 
b) Chemical dependent paraments(Partition coefficient, Metabolic rate, Excretion rate); Physiological-anatomical parameters(Blood flow, Body weight, Organ volumes); Exposure pattern(Dose, Frequence, Duration).
c) 
1. Describe question to be answered
2. Collect data
3. Define model
4. Validate and refine model
5. Answer question by simulation

a) from text book page 37

b) and c) from slides

12. Briefly describe two advantages and two disadvantages of noncompartmental toxicokinetic models.

Advantages:
(1) Model-independent – no assumptions about body physiology or chemical-specific parameters
(2) Less complex algebraic equations
(3) Fast and more cost-efficient

Disadvantage:
(1) No extrapolation between doses, time points, experimental models, etc.
(2) does not reflect population characteristics with persons of different age, ethnicity, disease status, genetic polymorphism, etc.
(3) Exposure characteristic is often missing in environmental studies

From slides