Significance of protein binding in drug action MCQs With Answer

Introduction

The following set of multiple-choice questions focuses on the significance of protein binding in drug action, tailored for M.Pharm students in Advanced Pharmacology-I. These questions explore how plasma protein binding influences pharmacokinetics (distribution, clearance, half-life), pharmacodynamics (free drug hypothesis, therapeutic effect), and clinical implications (drug–drug interactions, disease states, neonatal considerations). Emphasis is placed on mechanistic understanding—how changes in binding alter free fraction, total versus unbound concentrations, and when displacement is clinically meaningful. Use these MCQs to test and deepen your knowledge of protein–drug interactions, assay interpretation, and safe therapeutic decision-making when protein binding is an important determinant of drug behavior.

Q1. Which plasma protein primarily binds acidic drugs such as warfarin and many nonsteroidal anti-inflammatory drugs?

• Alpha-1-acid glycoprotein
• Globulins
• Albumin
• Lipoproteins

Correct Answer: Albumin

Q2. What is the pharmacologically active fraction of a drug in plasma according to the free drug hypothesis?

• Total plasma concentration (bound + unbound)
• Protein-bound fraction only
• Unbound (free) drug concentration
• Drug concentration in red blood cells

Correct Answer: Unbound (free) drug concentration

Q3. Fraction unbound (fu) is best defined as:

• Concentration of drug bound to albumin divided by total plasma concentration
• Concentration of unbound drug divided by total plasma concentration
• Volume of distribution divided by plasma volume
• Clearance divided by bioavailability

Correct Answer: Concentration of unbound drug divided by total plasma concentration

Q4. A highly protein-bound drug (99% bound) is displaced by another drug, increasing its fu from 0.01 to 0.02. Which statement is true immediately after displacement assuming no change in clearance?

• Total plasma concentration doubles and free concentration remains unchanged
• Free concentration doubles while total concentration decreases slightly
• Total plasma concentration remains the same and free concentration doubles
• Both free and total concentrations remain unchanged

Correct Answer: Free concentration doubles while total concentration decreases slightly

Q5. Which analytical method is commonly used to measure the unbound fraction of a drug in plasma?

• Mass spectrometry without separation
• Equilibrium dialysis
• Thin-layer chromatography
• Gas chromatography with derivatization

Correct Answer: Equilibrium dialysis

Q6. Alpha-1-acid glycoprotein primarily binds which type of drugs?

• Acidic drugs
• Basic (cationic) drugs
• Neutral lipophilic drugs
• Highly ionized peptides

Correct Answer: Basic (cationic) drugs

Q7. How does an increase in protein binding generally affect the apparent volume of distribution (Vd) of a drug?

• Increases Vd because more drug is transported to tissues
• Decreases Vd because more drug is retained in plasma bound to proteins
• No change in Vd because binding is independent of distribution
• Causes unpredictable changes in Vd due to protein turnover

Correct Answer: Decreases Vd because more drug is retained in plasma bound to proteins

Q8. In hypoalbuminemia, what is the usual immediate effect on the total and unbound drug concentrations for a highly albumin-bound acidic drug, before any compensatory elimination changes?

• Total concentration increases; unbound concentration decreases
• Total concentration decreases; unbound concentration increases
• Both total and unbound concentrations increase equally
• Both total and unbound concentrations remain unchanged

Correct Answer: Total concentration decreases; unbound concentration increases

Q9. Which clinical scenario makes a drug–drug displacement interaction most likely to be clinically important?

• Drug A is highly protein bound, has a wide therapeutic index, and high hepatic extraction
• Drug A is highly protein bound, narrow therapeutic index, and low clearance
• Drug A is minimally protein bound and cleared renally unchanged
• Drug A is highly water soluble with rapid renal elimination

Correct Answer: Drug A is highly protein bound, narrow therapeutic index, and low clearance

Q10. Which statement best explains why displacement of a drug from plasma proteins does not always lead to increased pharmacological effect?

• Displaced drug is immediately bound to tissue proteins and inactivated
• Clearance mechanisms often increase to remove the additional free drug, re-establishing equilibrium
• Displacement only changes volume of distribution, not free concentration
• Only bound drug is pharmacologically active, so displacement reduces effect

Correct Answer: Clearance mechanisms often increase to remove the additional free drug, re-establishing equilibrium

Q11. Nonlinear protein binding at therapeutic concentrations can contribute to which pharmacokinetic phenomenon?

• Zero-order elimination due to saturable metabolic enzymes
• Linear increase in total concentration with dose
• Disproportionate increases in free and total concentration with dose (concentration-dependent fu)
• Complete lack of tissue distribution regardless of lipophilicity

Correct Answer: Disproportionate increases in free and total concentration with dose (concentration-dependent fu)

Q12. Which mathematical relationship links unbound clearance (CLu), total clearance (CL), and fraction unbound (fu)?

• CLu = CL × fu
• CL = CLu × fu
• fu = CL / CLu
• CLu = CL / fu

Correct Answer: CLu = CL / fu

Q13. For a drug with high hepatic extraction ratio, how does a change in plasma protein binding typically affect hepatic clearance?

• Protein binding changes have little effect on hepatic clearance because clearance is flow-limited
• Increased binding proportionally increases hepatic clearance
• Decreased binding eliminates hepatic clearance entirely
• Protein binding changes convert hepatic clearance to renal clearance

Correct Answer: Protein binding changes have little effect on hepatic clearance because clearance is flow-limited

Q14. Which clinical laboratory measurement can be misleading if only total drug concentration is reported for a highly protein-bound drug?

• Assessment of electrolyte balance
• Interpretation of pharmacologic effect or toxicity risk
• Blood glucose estimation
• Complete blood count accuracy

Correct Answer: Interpretation of pharmacologic effect or toxicity risk

Q15. In pregnancy, plasma protein concentrations change. How does increased plasma volume and decreased albumin typically affect free concentrations of highly albumin-bound drugs?

• Free concentration usually decreases due to dilution and increased clearance
• Free concentration increases because decreased albumin raises fu, though total concentration may fall
• No change in free concentration because free drug is tightly regulated by the placenta
• Total concentration increases while free concentration is unchanged

Correct Answer: Free concentration increases because decreased albumin raises fu, though total concentration may fall

Q16. Which factor distinguishes tissue binding from plasma protein binding in affecting volume of distribution?

• Tissue binding only affects clearance, not distribution
• Tissue binding can increase Vd by retaining drug in tissues, while plasma binding tends to restrict drug to plasma and reduce Vd
• Both tissue and plasma binding always reduce Vd equally
• Tissue binding prevents drug from crossing membranes, decreasing Vd

Correct Answer: Tissue binding can increase Vd by retaining drug in tissues, while plasma binding tends to restrict drug to plasma and reduce Vd

Q17. Which property of a drug makes it most likely to be extensively bound to plasma proteins?

• High water solubility and ionization at physiological pH
• High lipophilicity and presence of acidic or basic functional groups
• Extremely low molecular weight (<100 Da)
• Complete renal elimination as unchanged drug

Correct Answer: High lipophilicity and presence of acidic or basic functional groups

Q18. When interpreting therapeutic drug monitoring (TDM) for a highly protein-bound drug in a patient with uremia, which adjustment is most appropriate?

• Use total drug concentration without adjustment because binding is unchanged in uremia
• Measure or estimate unbound concentration because uremic toxins can displace drugs from proteins
• Rely on urine concentrations only to assess exposure
• Ignore protein binding and double the dosing interval

Correct Answer: Measure or estimate unbound concentration because uremic toxins can displace drugs from proteins

Q19. Which experimental observation would indicate saturable (nonlinear) plasma protein binding at therapeutic concentrations?

• fu remains constant across a wide range of concentrations
• Total concentration increases proportionally with dose while fu decreases
• fu increases as concentration increases, with disproportionate rise in unbound concentration
• Drug shows first-order elimination kinetics at all concentrations

Correct Answer: fu increases as concentration increases, with disproportionate rise in unbound concentration

Q20. Why is protein binding particularly important to consider for drugs with a narrow therapeutic index?

• Bound drug causes most of the toxicity, so increased binding raises risk
• Small changes in free fraction can lead to large changes in unbound concentration and toxicity or loss of efficacy
• Narrow therapeutic index drugs are always hydrophilic and not protein bound
• Protein binding protects against drug interactions, so it is less important

Correct Answer: Small changes in free fraction can lead to large changes in unbound concentration and toxicity or loss of efficacy

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