Welcome, PharmD students, to this MCQ quiz on Hepatic Clearance! The liver plays a crucial role in drug metabolism and elimination, significantly impacting a drug’s efficacy and safety. Understanding hepatic clearance—how the liver removes drugs from the blood—and the factors that influence it, such as blood flow, protein binding, and intrinsic enzyme activity, is vital for predicting drug behavior and individualizing therapy. This quiz will test your knowledge of high and low extraction ratio drugs, the first-pass effect, and the clinical implications of altered hepatic function. Let’s explore the complexities of how the liver handles medications!
1. Hepatic clearance (Clh) refers to the:
- a) Rate at which a drug is absorbed from the gastrointestinal tract.
- b) Volume of blood or plasma completely cleared of a drug by the liver per unit of time.
- c) Fraction of drug eliminated by the kidneys.
- d) Time it takes for the plasma drug concentration to reduce by half due to liver function.
Answer: b) Volume of blood or plasma completely cleared of a drug by the liver per unit of time.
2. The three main physiological factors determining hepatic clearance according to the well-stirred model are hepatic blood flow (Qh), fraction of unbound drug (fu), and:
- a) Renal blood flow
- b) Intrinsic clearance (Clint)
- c) Glomerular filtration rate
- d) Bile flow rate
Answer: b) Intrinsic clearance (Clint)
3. The hepatic extraction ratio (E) is defined as the:
- a) Fraction of drug bound to plasma proteins.
- b) Fraction of drug absorbed after oral administration.
- c) Fraction of drug removed from the blood during a single pass through the liver.
- d) Ratio of drug concentration in bile to drug concentration in plasma.
Answer: c) Fraction of drug removed from the blood during a single pass through the liver.
4. For a drug with a high hepatic extraction ratio (E > 0.7), its hepatic clearance is primarily dependent on:
- a) Intrinsic clearance (Clint)
- b) Fraction of unbound drug (fu)
- c) Hepatic blood flow (Qh)
- d) Renal function
Answer: c) Hepatic blood flow (Qh)
5. Drugs with high hepatic extraction ratios are often referred to as:
- a) Capacity-limited drugs
- b) Flow-limited drugs
- c) Binding-sensitive drugs
- d) Renally eliminated drugs
Answer: b) Flow-limited drugs
6. For a drug with a low hepatic extraction ratio (E < 0.3), its hepatic clearance is primarily dependent on:
- a) Hepatic blood flow (Qh) only.
- b) Fraction of unbound drug (fu) and intrinsic clearance (Clint).
- c) Only the dose administered.
- d) Only its molecular weight.
Answer: b) Fraction of unbound drug (fu) and intrinsic clearance (Clint).
7. Drugs with low hepatic extraction ratios are often referred to as:
- a) Flow-limited drugs
- b) Perfusion-dependent drugs
- c) Capacity-limited drugs (or enzyme-limited drugs)
- d) Blood-flow independent drugs
Answer: c) Capacity-limited drugs (or enzyme-limited drugs)
8. Intrinsic clearance (Clint) represents the:
- a) Rate of blood flow to the liver.
- b) Maximum ability of the liver to metabolize a drug in the absence of blood flow limitations and protein binding.
- c) Fraction of drug bound to liver tissue.
- d) Rate of drug excretion into the bile.
Answer: b) Maximum ability of the liver to metabolize a drug in the absence of blood flow limitations and protein binding.
9. The “first-pass effect” (presystemic metabolism) is most significant for orally administered drugs that:
- a) Are primarily excreted unchanged by the kidneys.
- b) Have a very low hepatic extraction ratio.
- c) Have a very high hepatic extraction ratio.
- d) Are administered intravenously.
Answer: c) Have a very high hepatic extraction ratio.
10. If a drug has a hepatic extraction ratio (E) of 0.8, what is its estimated oral bioavailability (F) assuming all absorbed drug passes through the liver and is only eliminated by hepatic metabolism?
- a) 0.8 (80%)
- b) 1.0 (100%)
- c) 0.2 (20%)
- d) 0.5 (50%)
Answer: c) 0.2 (20%) (F = 1 – E)
11. Enzyme induction (e.g., by rifampin) will most significantly increase the hepatic clearance of which type of drug?
- a) A high extraction ratio drug whose clearance is flow-limited.
- b) A low extraction ratio drug whose clearance is dependent on intrinsic clearance.
- c) A drug primarily eliminated by renal excretion.
- d) A drug that is not metabolized.
Answer: b) A low extraction ratio drug whose clearance is dependent on intrinsic clearance.
12. Enzyme inhibition (e.g., by cimetidine) will most significantly decrease the hepatic clearance of which type of drug?
- a) A high extraction ratio drug whose clearance is flow-limited.
- b) A low extraction ratio drug whose clearance is dependent on intrinsic clearance.
- c) A drug whose clearance is primarily dependent on hepatic blood flow.
- d) A drug eliminated only by glomerular filtration.
Answer: b) A low extraction ratio drug whose clearance is dependent on intrinsic clearance.
13. For a high extraction ratio drug, a decrease in hepatic blood flow (e.g., in heart failure) will likely lead to:
- a) A significant increase in its hepatic clearance.
- b) A significant decrease in its hepatic clearance and potentially increased oral bioavailability.
- c) No change in its hepatic clearance.
- d) A primary effect on its renal clearance.
Answer: b) A significant decrease in its hepatic clearance and potentially increased oral bioavailability.
14. For a low extraction ratio drug with high plasma protein binding, a decrease in protein binding (e.g., due to hypoalbuminemia or displacement) will:
- a) Decrease its intrinsic clearance.
- b) Increase its fraction unbound (fu), potentially increasing its hepatic clearance (if Clint is not saturated).
- c) Always decrease its hepatic clearance.
- d) Have no effect on its hepatic clearance.
Answer: b) Increase its fraction unbound (fu), potentially increasing its hepatic clearance (if Clint is not saturated). (This is for “restrictive” low E drugs. For non-restrictive, fu change has less impact on CL). Let’s make this more specific.
Revised Question 14: 14. For a low extraction ratio drug whose clearance is “restrictively” dependent on the free drug concentration, a decrease in plasma protein binding will likely lead to:
- a) Decreased hepatic clearance.
- b) Increased hepatic clearance because fuClint increases.
- c) No change in hepatic clearance.
- d) Increased hepatic blood flow.
Answer: b) Increased hepatic clearance because fuClint increases.
15. The well-stirred model of hepatic clearance assumes that:
- a) Drug concentration is uniform throughout the liver sinusoids and equal to the outgoing venous blood concentration.
- b) Drug metabolism occurs only in the portal vein.
- c) Liver blood flow does not affect clearance.
- d) All drugs are cleared non-restrictively.
Answer: a) Drug concentration is uniform throughout the liver sinusoids and equal to the outgoing venous blood concentration.
16. “Non-restrictive” hepatic clearance implies that:
- a) Only the free (unbound) drug is cleared by the liver.
- b) Both free and bound drug can be efficiently extracted by the liver, often seen with high Clint drugs or active uptake.
- c) Protein binding completely prevents hepatic clearance.
- d) The drug is not metabolized by the liver.
Answer: b) Both free and bound drug can be efficiently extracted by the liver, often seen with high Clint drugs or active uptake.
17. A decrease in intrinsic clearance (Clint) due to liver disease would have the most pronounced effect on the hepatic clearance of:
- a) High extraction ratio, flow-limited drugs.
- b) Low extraction ratio, capacity-limited drugs.
- c) Drugs eliminated solely by renal mechanisms.
- d) Drugs administered via IV route only.
Answer: b) Low extraction ratio, capacity-limited drugs.
18. If hepatic clearance (Clh) is calculated as Qh × E, and E = (fu × Clint) / (Qh + fu × Clint), this equation is part of the:
- a) Parallel tube model
- b) Dispersion model
- c) Well-stirred (venous equilibrium) model
- d) One-compartment pharmacokinetic model
Answer: c) Well-stirred (venous equilibrium) model
19. For a high extraction ratio drug, what is the primary factor influencing its oral bioavailability (F)?
- a) Gastric emptying time.
- b) Hepatic blood flow (indirectly, as E is high, so F = 1-E will be low).
- c) Intrinsic clearance (Clint) (less directly than E).
- d) The hepatic extraction ratio (E), which is largely determined by Clint being much greater than Qh.
Answer: d) The hepatic extraction ratio (E), which is largely determined by Clint being much greater than Qh. (F = 1-E; for high E drugs, F will be low).
20. If a patient with cirrhosis experiences a significant decrease in liver blood flow, which type of drug will show the most substantial decrease in systemic clearance?
- a) A low extraction ratio drug primarily metabolized by CYP2D6.
- b) A high extraction ratio drug.
- c) A drug eliminated primarily by the kidneys.
- d) A drug that is not protein-bound.
Answer: b) A high extraction ratio drug.
21. The fraction of unbound drug (fu) is important in hepatic clearance because:
- a) Only bound drug can be metabolized by liver enzymes.
- b) Only unbound drug is generally thought to be available to interact with metabolizing enzymes and transporters.
- c) It determines the rate of liver blood flow.
- d) It is equal to the extraction ratio.
Answer: b) Only unbound drug is generally thought to be available to interact with metabolizing enzymes and transporters. (for restrictive clearance)
22. For a low extraction ratio drug that is highly protein bound, enzyme induction would lead to:
- a) A large increase in total clearance if unbound clearance increases significantly.
- b) A small or negligible increase in total clearance.
- c) A decrease in total clearance.
- d) No change in intrinsic clearance.
Answer: a) A large increase in total clearance if unbound clearance increases significantly. (Clh ≈ fu * Clint. If Clint increases, Clh increases).
23. A drug that undergoes significant biliary excretion contributes to:
- a) Only renal clearance.
- b) Hepatic clearance (as part of overall liver elimination processes).
- c) Pulmonary clearance.
- d) Metabolic clearance only.
Answer: b) Hepatic clearance (as part of overall liver elimination processes).
24. The oral bioavailability (F) of a drug subject to first-pass hepatic metabolism can be improved by:
- a) Increasing the dose, which saturates the metabolic enzymes (if capacity-limited).
- b) Administering the drug with an enzyme inhibitor.
- c) Administering the drug with food that increases liver blood flow (for some high E drugs).
- d) All of the above under specific circumstances.
Answer: d) All of the above under specific circumstances. (a is for capacity-limited metabolism, b for enzyme inhibition, c for some high E drugs, though food effects are complex).
25. If a drug has an intrinsic clearance (Clint) much greater than hepatic blood flow (Qh), it is likely to be a:
- a) Low extraction ratio drug.
- b) High extraction ratio drug.
- c) Drug eliminated only by the kidneys.
- d) Drug with poor membrane permeability.
Answer: b) High extraction ratio drug. (E ≈ Qh / (Qh + fuClint) if fuClint >> Qh then E approaches 1; or simplified E ≈ fu*Clint / Qh is not correct. Simplified for high E: E ≈ 1 when Clint >> Qh. Another view Clh ≈ Qh when Clint is very high). Let’s use the common definition: if Clint is very high, the liver can clear it as fast as it’s delivered, so E is high.
26. Changes in plasma protein binding will have the most significant impact on the clearance of:
- a) High extraction ratio drugs with restrictive clearance.
- b) Low extraction ratio drugs with restrictive clearance and high protein binding.
- c) Drugs that are not protein bound.
- d) Drugs cleared by non-restrictive mechanisms.
Answer: b) Low extraction ratio drugs with restrictive clearance and high protein binding.
27. Liver disease can affect hepatic clearance by:
- a) Only increasing liver blood flow.
- b) Decreasing intrinsic enzyme activity, reducing liver blood flow, and altering protein binding.
- c) Only decreasing protein binding.
- d) Only increasing biliary excretion.
Answer: b) Decreasing intrinsic enzyme activity, reducing liver blood flow, and altering protein binding.
28. For a drug with flow-limited hepatic clearance, what would happen to its systemic clearance if cardiac output (and thus liver blood flow) doubles?
- a) Systemic clearance would halve.
- b) Systemic clearance would approximately double.
- c) Systemic clearance would remain unchanged.
- d) Systemic clearance would increase only marginally.
Answer: b) Systemic clearance would approximately double.
29. The concept of “shunting” in liver disease refers to:
- a) Increased blood flow directly through the liver sinusoids.
- b) Blood bypassing the functional liver tissue (hepatocytes), reducing effective drug delivery for metabolism.
- c) Enhanced biliary excretion.
- d) Increased protein binding.
Answer: b) Blood bypassing the functional liver tissue (hepatocytes), reducing effective drug delivery for metabolism.
30. If a drug is subject to non-restrictive hepatic clearance, its extraction by the liver:
- a) Is limited by the unbound drug concentration only.
- b) Is very efficient and can exceed the rate predicted by free drug concentration alone, implying bound drug can also be stripped off proteins.
- c) Is always less than 0.3.
- d) Is independent of intrinsic clearance.
Answer: b) Is very efficient and can exceed the rate predicted by free drug concentration alone, implying bound drug can also be stripped off proteins.
31. Predicting drug clearance based on its extraction ratio is important for:
- a) Determining the drug’s color.
- b) Anticipating the effects of physiological changes (e.g., blood flow, enzyme activity) or drug interactions on drug exposure.
- c) Choosing the packaging of the drug.
- d) Deciding the brand name.
Answer: b) Anticipating the effects of physiological changes (e.g., blood flow, enzyme activity) or drug interactions on drug exposure.
32. The oral clearance (Cl/F) of a drug is calculated as Dose_oral / AUC_oral. If F is low due to high first-pass metabolism, Cl/F will be:
- a) Lower than the true systemic clearance (Cl).
- b) Higher than the true systemic clearance (Cl).
- c) Equal to the true systemic clearance (Cl).
- d) Unrelated to systemic clearance.
Answer: b) Higher than the true systemic clearance (Cl).
33. For a low extraction ratio drug whose clearance is mainly determined by fu * Clint, if fu doubles and Clint remains constant, the hepatic clearance will approximately:
- a) Halve
- b) Double
- c) Remain unchanged
- d) Increase four-fold
Answer: b) Double
34. In cases of severe liver disease, the half-life of a hepatically cleared drug is often prolonged due to:
- a) Decreased volume of distribution.
- b) Decreased clearance (due to reduced Clint and/or Qh).
- c) Increased protein binding.
- d) Enhanced renal excretion as a compensatory mechanism.
Answer: b) Decreased clearance (due to reduced Clint and/or Qh).
35. A drug that is a potent enzyme inducer will cause _______ in the intrinsic clearance of other drugs metabolized by that enzyme.
- a) A decrease
- b) An increase
- c) No change
- d) A temporary fluctuation
Answer: b) An increase
36. What is the relationship between hepatic extraction ratio (E) and hepatic clearance (Clh) and hepatic blood flow (Qh)?
- a) Clh = Qh / E
- b) Clh = E / Qh
- c) Clh = Qh * E
- d) Clh = Qh – E
Answer: c) Clh = Qh * E
37. If the intrinsic clearance (fu * Clint) is much smaller than hepatic blood flow (Qh), the drug is likely a:
- a) High extraction ratio drug
- b) Low extraction ratio drug
- c) Drug not cleared by the liver
- d) Drug with very high bioavailability regardless of metabolism
Answer: b) Low extraction ratio drug (Clh ≈ fu * Clint)
38. The first-pass effect specifically reduces the bioavailability of drugs administered via the:
- a) Intravenous route
- b) Oral route (and other routes draining into the portal circulation before systemic access)
- c) Transdermal route
- d) Sublingual route (largely bypasses it)
Answer: b) Oral route (and other routes draining into the portal circulation before systemic access)
39. For a drug with a high hepatic extraction ratio, changes in plasma protein binding have:
- a) A significant impact on its total hepatic clearance.
- b) Little to no impact on its total hepatic clearance (if clearance is non-restrictive or primarily flow-limited).
- c) Only an impact on its renal clearance.
- d) An impact only if the drug is acidic.
Answer: b) Little to no impact on its total hepatic clearance (if clearance is non-restrictive or primarily flow-limited). (Total Clh ≈ Qh)
40. Clinical situations that can decrease hepatic blood flow include:
- a) Vigorous exercise
- b) Heart failure, shock, or use of beta-blockers
- c) Consumption of a large meal (often increases splanchnic blood flow)
- d) Hyperthyroidism
Answer: b) Heart failure, shock, or use of beta-blockers
41. If a low extraction drug is a substrate for an enzyme that gets inhibited, its AUC after oral administration will likely:
- a) Decrease
- b) Increase
- c) Remain unchanged
- d) Fluctuate unpredictably
Answer: b) Increase (Due to decreased clearance and potentially increased F if first-pass is also affected).
42. The term “restrictive clearance” usually applies to drugs where:
- a) The liver can clear both bound and unbound drug.
- b) Only the unbound fraction of the drug is available for hepatic uptake and metabolism.
- c) Clearance is limited by blood flow.
- d) The drug is excreted unchanged in urine.
Answer: b) Only the unbound fraction of the drug is available for hepatic uptake and metabolism.
43. Understanding a drug’s hepatic extraction ratio is crucial when considering:
- a) The likelihood of significant first-pass metabolism for an oral dose.
- b) The potential impact of changes in liver blood flow on its clearance.
- c) The sensitivity of its clearance to enzyme induction or inhibition.
- d) All of the above.
Answer: d) All of the above.
44. If a drug’s hepatic clearance is capacity-limited, this means it is primarily dictated by:
- a) How fast the drug is delivered to the liver (blood flow).
- b) The liver’s inherent ability to metabolize the drug (enzyme activity).
- c) The rate of glomerular filtration.
- d) The drug’s pKa.
Answer: b) The liver’s inherent ability to metabolize the drug (enzyme activity).
45. A drug with E = 0.5 would be considered an:
- a) High extraction ratio drug
- b) Low extraction ratio drug
- c) Intermediate extraction ratio drug
- d) Drug not extracted by the liver
Answer: c) Intermediate extraction ratio drug
46. For a drug with flow-limited clearance, an increase in hepatic blood flow (e.g., after a meal for some drugs) might lead to:
- a) Decreased clearance
- b) Increased clearance
- c) No change in clearance
- d) Decreased bioavailability
Answer: b) Increased clearance
47. When predicting the impact of liver disease on drug dosing, it’s important to consider:
- a) Only the Child-Pugh score.
- b) The specific drug’s pharmacokinetic profile (e.g., extraction ratio, primary metabolic pathways affected).
- c) Only the patient’s age.
- d) Only whether the drug is acidic or basic.
Answer: b) The specific drug’s pharmacokinetic profile (e.g., extraction ratio, primary metabolic pathways affected).
48. If the oral bioavailability (F) of a drug is 0.1 due to extensive first-pass hepatic metabolism, this implies its hepatic extraction ratio (E) is approximately:
- a) 0.1
- b) 0.5
- c) 0.9
- d) 0.01
Answer: c) 0.9 (Since F ≈ 1 – E)
49. In the well-stirred model, if fu * Clint << Qh, then Clh approximates:
- a) Qh
- b) fu * Clint
- c) Clint
- d) Qh / fu
Answer: b) fu * Clint (This describes a low extraction, capacity-limited, restrictively cleared drug)
50. The main clinical relevance of understanding hepatic clearance mechanisms for a pharmacist is to:
- a) Compound medications more effectively.
- b) Anticipate and manage dose adjustments, drug interactions, and effects of organ dysfunction on drug therapy.
- c) Decide on the drug’s approved indications.
- d) Perform liver function tests in the pharmacy.
Answer: b) Anticipate and manage dose adjustments, drug interactions, and effects of organ dysfunction on drug therapy.