PEBC Pharmacokinetics and Drug Metabolism — Questions and Answers
Question 1: A drug has a half-life of 8 hours and follows first-order kinetics. Approximately how long does it take to reach steady-state plasma concentration when administered at regular dosing intervals?
- 8 hours (one half-life)
- 16 hours (two half-lives)
- 40 hours (five half-lives) (Correct answer)
- 80 hours (ten half-lives)
Correct answer: 40 hours (five half-lives)
For first-order kinetics, steady-state is achieved after approximately 4–5 half-lives regardless of dose or dosing interval. With a half-life of 8 hours, steady-state is reached in approximately 5 × 8 = 40 hours.
Question 2: A patient with severe renal impairment (CrCl < 15 mL/min) is prescribed a drug that is 90% renally eliminated unchanged. Which dosing adjustment is MOST appropriate?
- No adjustment needed; renal impairment does not affect renally eliminated drugs
- Increase the dose to compensate for reduced absorption
- Reduce the dose and/or extend the dosing interval to prevent drug accumulation (Correct answer)
- Switch to IV administration to bypass renal elimination
Correct answer: Reduce the dose and/or extend the dosing interval to prevent drug accumulation
Drugs highly dependent on renal elimination accumulate in patients with renal impairment because the kidneys cannot clear the drug efficiently. The dose must be reduced and/or the interval extended to maintain safe plasma concentrations and avoid toxicity.
Question 3: Which cytochrome P450 enzyme is responsible for metabolizing the greatest number of clinically used drugs, making it the most clinically significant source of drug-drug interactions?
- CYP1A2
- CYP2C9
- CYP3A4 (Correct answer)
- CYP2D6
Correct answer: CYP3A4
CYP3A4 is the most abundant CYP enzyme in the liver and intestine and metabolizes approximately 50% of clinically used drugs. It is the most common source of pharmacokinetic drug-drug interactions through induction or inhibition.
Question 4: A pharmacist calculates that a drug has a volume of distribution (Vd) of 500 L in a 70 kg patient. What does this large Vd indicate?
- The drug is highly concentrated in the plasma with minimal tissue distribution
- The drug is extensively distributed into peripheral tissues or fat (Correct answer)
- The drug has poor oral bioavailability
- The drug is rapidly eliminated by the kidneys
Correct answer: The drug is extensively distributed into peripheral tissues or fat
A large Vd (much greater than total body water of ~42 L) indicates that the drug distributes extensively outside the plasma into peripheral tissues, body fat, or binds intracellularly. Small Vd values suggest the drug stays primarily in the plasma.
Question 5: A patient is taking phenytoin, which follows zero-order (saturable) kinetics at therapeutic doses. How does this differ from first-order kinetics in clinical practice?
- A fixed amount of drug is eliminated per unit time; small dose increases can cause disproportionately large rises in plasma concentration (Correct answer)
- A fixed proportion of drug is eliminated per unit time; dose increases cause proportional rises in plasma concentration
- Zero-order drugs are eliminated faster than first-order drugs at all concentrations
- Zero-order kinetics means the drug is not metabolized by the liver
Correct answer: A fixed amount of drug is eliminated per unit time; small dose increases can cause disproportionately large rises in plasma concentration
Zero-order (saturable) kinetics means the metabolic enzymes are saturated; a constant amount (not proportion) is eliminated per unit time. Small dose increases in the therapeutic range can cause dramatic, disproportionate increases in plasma levels, significantly raising toxicity risk with phenytoin.
Question 6: A patient with hepatic cirrhosis requires a drug that undergoes extensive first-pass metabolism. How does cirrhosis typically affect the bioavailability of this drug?
- Bioavailability decreases because the liver degrades the drug more rapidly
- Bioavailability increases because first-pass metabolism is reduced, allowing more drug to reach systemic circulation (Correct answer)
- Bioavailability is unaffected because the kidneys compensate for reduced hepatic metabolism
- Bioavailability decreases because portal hypertension reduces GI absorption
Correct answer: Bioavailability increases because first-pass metabolism is reduced, allowing more drug to reach systemic circulation
First-pass metabolism occurs in the liver before a drug reaches systemic circulation. In hepatic cirrhosis, functional liver mass is reduced and portosystemic shunting bypasses the liver, significantly reducing first-pass metabolism and increasing bioavailability — potentially to toxic levels.
PEBC Pharmacokinetics and Drug Metabolism
A drug has a half-life of 8 hours and follows first-order kinetics.
Approximately how long does it take to reach steady-state plasma concentration when administered at regular dosing intervals?