Toxicokinetics: role in preclinical studies MCQs With Answer

Toxicokinetics: role in preclinical studies MCQs With Answer

This quiz collection is designed for M.Pharm students preparing for advanced topics in toxicokinetics within preclinical drug development. It focuses on principles of absorption, distribution, metabolism and excretion (ADME) as they relate to toxicity assessment, dose selection, species differences, and modelling approaches such as PBTK and IVIVE. Questions emphasize interpretation of toxicokinetic parameters, study design considerations (sampling, bioanalytical limits), nonlinear kinetics, and prediction of human risk from animal data. Use these MCQs to strengthen conceptual understanding and practical decision-making for safety pharmacology and regulatory toxicology in preclinical studies.

Q1. Which toxicokinetic parameter best describes the extent to which a compound distributes into tissues relative to plasma?

• Clearance (CL)
• Volume of distribution (Vd)
• Bioavailability (F)
• Elimination rate constant (ke)

Correct Answer: Volume of distribution (Vd)

Q2. In preclinical toxicokinetic studies, measuring plasma protein binding is important because:

• Only unbound drug is filtered by the kidney and available for tissue distribution
• Bound drug determines the oral absorption rate
• Protein binding increases the intrinsic metabolic rate
• It directly reflects the volume of distribution magnitude

Correct Answer: Only unbound drug is filtered by the kidney and available for tissue distribution

Q3. Nonlinear (saturable) kinetics in toxicokinetics often result from:

• First-order renal excretion unaffected by concentration
• Saturation of metabolic enzymes or transporters at higher doses
• Constant hepatic blood flow regardless of dose
• Proportional plasma protein binding across concentrations

Correct Answer: Saturation of metabolic enzymes or transporters at higher doses

Q4. Physiologically based toxicokinetic (PBTK) models are particularly useful in preclinical studies because they:

• Require no biological or anatomical parameters
• Allow extrapolation across species and doses using physiology and mechanism
• Replace the need for any in vivo studies completely
• Assume all tissues have identical partitioning coefficients

Correct Answer: Allow extrapolation across species and doses using physiology and mechanism

Q5. Which sampling strategy is most appropriate to accurately estimate terminal half-life in a toxicokinetic study?

• Frequent early sampling only during absorption phase
• Sparse sampling confined to the first hour post-dose
• Extended sampling to capture the terminal elimination phase
• Single time point at Tmax

Correct Answer: Extended sampling to capture the terminal elimination phase

Q6. Interspecies allometric scaling of clearance commonly uses which body-size related variable?

• Absolute organ weights only
• Body surface area without exponentiation
• Body weight with an exponent (e.g., 0.75)
• Drug lipophilicity (log P) as the main factor

Correct Answer: Body weight with an exponent (e.g., 0.75)

Q7. A major reason to perform toxicokinetic analysis at the maximum tolerated dose (MTD) in animals is to:

• Ensure linear kinetics at all doses
• Characterize exposures at doses that produce toxicity for hazard assessment
• Minimize required analytical sensitivity
• Avoid any metabolism by hepatic enzymes

Correct Answer: Characterize exposures at doses that produce toxicity for hazard assessment

Q8. Bioavailability (F) is defined as:

• The rate of elimination divided by dose
• The fraction of administered dose reaching the systemic circulation unchanged
• The volume into which the drug distributes per unit body weight
• The unbound fraction in plasma

Correct Answer: The fraction of administered dose reaching the systemic circulation unchanged

Q9. Enterohepatic recirculation affects toxicokinetic profiles primarily by:

• Eliminating drug faster via lungs
• Creating secondary peaks and prolonging apparent half-life
• Increasing first-pass hepatic extraction proportionally
• Preventing biliary excretion entirely

Correct Answer: Creating secondary peaks and prolonging apparent half-life

Q10. In vitro-in vivo extrapolation (IVIVE) in toxicokinetics is used to:

• Predict human or animal systemic clearance from in vitro metabolic data
• Measure plasma proteins directly in vivo
• Replace PBTK modeling altogether
• Determine Tmax without in vivo studies

Correct Answer: Predict human or animal systemic clearance from in vitro metabolic data

Q11. Which parameter is most informative to compare systemic exposure between different dose groups in a repeated-dose toxicology study?

• Clearance at a single time point
• Area under the plasma concentration–time curve (AUC)
• Single concentration measurement at 30 minutes
• Protein binding at baseline only

Correct Answer: Area under the plasma concentration–time curve (AUC)

Q12. When a metabolite is more toxic than the parent compound, toxicokinetic studies should prioritize:

• Only measuring parent compound concentrations
• Characterizing formation, clearance, and tissue distribution of the metabolite
• Excluding hepatic metabolism studies
• Assuming metabolite exposure equals parent exposure

Correct Answer: Characterizing formation, clearance, and tissue distribution of the metabolite

Q13. Saturation of renal tubular secretion would most likely cause which change in plasma concentration versus dose?

• Proportional decrease in plasma concentration with dose
• Disproportionately higher plasma concentrations at higher doses
• Elimination becoming faster as dose increases
• Complete elimination independent of dose

Correct Answer: Disproportionately higher plasma concentrations at higher doses

Q14. Which experimental approach helps determine whether a compound crosses the placenta in preclinical reproductive toxicology?

• Measure compound in maternal plasma only
• Assess concentrations in fetal tissues or fetal plasma at relevant times
• Assume no transfer if compound is protein bound
• Rely solely on in vitro hepatocyte metabolism data

Correct Answer: Assess concentrations in fetal tissues or fetal plasma at relevant times

Q15. The term “toxicokinetic steady state” during repeated dosing refers to:

• The time when absorption ceases entirely
• When peak and trough concentrations fluctuate but mean concentrations are constant between dosing intervals
• A single concentration immediately after the first dose
• The point when clearance becomes zero

Correct Answer: When peak and trough concentrations fluctuate but mean concentrations are constant between dosing intervals

Q16. Which bioanalytical concern is most critical when interpreting low-level exposures in toxicokinetic studies?

• Large sample volumes only
• Limit of quantification (LOQ) and assay sensitivity and accuracy
• High Tmax variability inherently invalidates results
• Excluding internal standards for faster throughput

Correct Answer: Limit of quantification (LOQ) and assay sensitivity and accuracy

Q17. Metabolic activation leading to reactive intermediates is best evaluated by combining toxicokinetics with:

• Protein binding assays only
• In vitro covalent binding assays and glutathione trapping studies
• Measuring only unchanged drug in urine
• Neglecting tissue distribution studies

Correct Answer: In vitro covalent binding assays and glutathione trapping studies

Q18. For a compound with high hepatic extraction, which factor most strongly influences its systemic clearance?

• Plasma protein binding only
• Hepatic blood flow
• Renal filtration rate exclusively
• Gastrointestinal pH

Correct Answer: Hepatic blood flow

Q19. Which approach improves confidence in human risk predictions from animal toxicokinetic data?

• Ignoring species differences in metabolic pathways
• Integrating PBTK modelling, in vitro metabolism data and exposure matching across species
• Relying on single-dose animal data without scaling
• Assuming identical bioavailability across species without evidence

Correct Answer: Integrating PBTK modelling, in vitro metabolism data and exposure matching across species

Q20. In design of a preclinical toxicokinetic study to support dose selection, a key objective is to:

• Identify exposure levels (AUC/Cmax) associated with observed toxicities and margins to human exposure
• Ensure all doses have identical AUC values
• Exclude measurement of metabolites to save cost
• Only test a single time point per animal to maximize animal numbers

Correct Answer: Identify exposure levels (AUC/Cmax) associated with observed toxicities and margins to human exposure

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