ABT Toxicokinetics and Metabolism 2 — Questions and Answers
Question 1: Physiologically based pharmacokinetic (PBPK) modeling is most useful in toxicology for:
- Replacing all animal studies in drug development
- Extrapolating toxicokinetic data across species, routes, and dose levels (Correct answer)
- Predicting chemical reactivity with proteins
- Measuring receptor binding affinities in vitro
Correct answer: Extrapolating toxicokinetic data across species, routes, and dose levels
PBPK models use physiological parameters (organ volumes, blood flows) and chemical-specific parameters to extrapolate internal dose across species (animal to human), routes, and dose levels in risk assessment.
Question 2: CYP2D6 'poor metabolizers' (PMs) are at increased risk for toxicity from drugs that are CYP2D6 substrates because they:
- Have duplicated gene copies leading to ultra-rapid metabolism
- Lack functional CYP2D6 and cannot metabolize substrates to inactive metabolites (Correct answer)
- Have increased CYP3A4 activity compensating for CYP2D6 loss
- Show altered renal excretion of parent compounds
Correct answer: Lack functional CYP2D6 and cannot metabolize substrates to inactive metabolites
CYP2D6 poor metabolizers (5–10% of Caucasians) carry loss-of-function alleles and cannot efficiently metabolize substrates, leading to drug accumulation and increased toxicity risk.
Question 3: The area under the concentration-time curve (AUC) is directly proportional to which pharmacokinetic parameter?
- Peak concentration (Cmax)
- Bioavailability / clearance (F/CL) (Correct answer)
- Volume of distribution (Vd)
- Absorption rate constant (ka)
Correct answer: Bioavailability / clearance (F/CL)
AUC = F × Dose / CL; for a given dose and bioavailability, AUC is inversely proportional to clearance and directly represents total systemic exposure.
Question 4: Which process explains enterohepatic recirculation and its effect on drug half-life?
- Drugs are reabsorbed from intestinal secretions after biliary excretion, extending their half-life (Correct answer)
- Drugs are metabolized in the intestine before reaching the liver, reducing bioavailability
- Hepatic drug metabolism increases when portal blood flow increases
- Drugs are filtered by the kidney and returned to systemic circulation
Correct answer: Drugs are reabsorbed from intestinal secretions after biliary excretion, extending their half-life
Enterohepatic recirculation occurs when drugs excreted in bile into the intestine are deconjugated by gut bacteria and reabsorbed, creating a drug reservoir that extends apparent half-life.
Question 5: The Michaelis-Menten equation describes enzyme-mediated metabolism; at concentrations far below Km, metabolism approaches:
- Zero-order kinetics (constant rate)
- First-order kinetics (rate proportional to concentration) (Correct answer)
- Negative kinetics (inhibition)
- Saturation plateau (Vmax)
Correct answer: First-order kinetics (rate proportional to concentration)
When substrate concentration is far below Km (the Michaelis constant), the enzyme is far from saturated and the reaction velocity is approximately proportional to substrate concentration — i.e., pseudo-first-order kinetics.
Question 6: CYP1A1 induction by polycyclic aromatic hydrocarbons (PAHs) increases risk of carcinogenicity because:
- CYP1A1 directly alkylates DNA at G sites
- CYP1A1 converts PAH procarcinogens to reactive diol-epoxides that form DNA adducts (Correct answer)
- CYP1A1 inhibits DNA repair enzymes (PARP)
- CYP1A1 activates p53 tumor suppressor gene
Correct answer: CYP1A1 converts PAH procarcinogens to reactive diol-epoxides that form DNA adducts
CYP1A1 (induced by PAH-AhR signaling) converts PAH procarcinogens like benzo[a]pyrene to reactive diol-epoxide metabolites (BPDE) that form covalent DNA adducts leading to mutagenesis.
ABT Toxicokinetics and Metabolism 2
Physiologically based pharmacokinetic (PBPK) modeling is most useful in toxicology for: