Prodrug design is a focused area in pharmaceutical science where inactive or less-active derivatives are engineered to improve drug properties like solubility, stability, permeability, bioavailability, targeted delivery, and safety. B. Pharm students should grasp core concepts such as chemical and enzymatic bioconversion, promoiety selection, carrier-linked and bioprecursor strategies, ester and phosphate prodrugs, site-selective activation, and examples including enalapril, valacyclovir, oseltamivir, and capecitabine. Understanding pharmacokinetics, enzyme involvement, formulation and regulatory considerations is essential for rational prodrug design and clinical translation. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. What is the best definition of a prodrug?
- An inactive or less-active derivative that is converted in vivo to the active drug
- A drug formulation that releases the active drug immediately
- A metabolite formed after drug elimination
- An active drug that requires no metabolism
Correct Answer: An inactive or less-active derivative that is converted in vivo to the active drug
Q2. Which is a primary objective of prodrug design?
- To increase molecular weight only
- To improve properties such as oral bioavailability, solubility, stability, and targeting
- To make a drug more colored for identification
- To reduce manufacturing costs exclusively
Correct Answer: To improve properties such as oral bioavailability, solubility, stability, and targeting
Q3. Which of the following are recognized prodrug types?
- Carrier-linked prodrugs, bioprecursor prodrugs, and mutual prodrugs
- Nanoparticle prodrugs only
- Isotopic prodrugs exclusively
- Salt forms and hydrates
Correct Answer: Carrier-linked prodrugs, bioprecursor prodrugs, and mutual prodrugs
Q4. Which enzymes are commonly involved in enzymatic activation of prodrugs?
- Esterases, amidases, peptidases, and cytochrome P450 enzymes
- DNA polymerases and ribosomes
- Photosynthetic enzymes
- Cellulose synthase only
Correct Answer: Esterases, amidases, peptidases, and cytochrome P450 enzymes
Q5. Which statement about enalapril is correct?
- Enalapril is a prodrug converted to enalaprilat, the active ACE inhibitor
- Enalapril is the active form and enalaprilat is the prodrug
- Enalapril is an antibiotic
- Enalapril is activated by gut bacteria only
Correct Answer: Enalapril is a prodrug converted to enalaprilat, the active ACE inhibitor
Q6. Valacyclovir is a prodrug of which antiviral agent?
- Acyclovir
- Oseltamivir
- Ribavirin
- Ganciclovir
Correct Answer: Acyclovir
Q7. Codeine is bioactivated to morphine primarily by which enzyme?
- CYP2D6
- Acetylcholinesterase
- Monoamine oxidase
- Alcohol dehydrogenase
Correct Answer: CYP2D6
Q8. First-pass metabolism that affects oral bioavailability mainly occurs in which sites?
- Liver and intestinal wall
- Kidney and spleen
- Skin and lungs
- Bone marrow only
Correct Answer: Liver and intestinal wall
Q9. What is a promoiety in prodrug chemistry?
- The chemical group temporarily attached to the drug to modify properties and later removed in vivo
- A metabolite produced during excretion
- A solvent used in formulation
- An impurity from synthesis
Correct Answer: The chemical group temporarily attached to the drug to modify properties and later removed in vivo
Q10. Which linkage is most commonly used for rapid enzymatic hydrolysis by esterases?
- Ester linkage
- Ether linkage
- Aromatic ring
- Carbon–carbon single bond
Correct Answer: Ester linkage
Q11. Which of the following is a phosphate prodrug designed to increase water solubility for parenteral use?
- Fosphenytoin
- Diazepam
- Warfarin
- Ibuprofen
Correct Answer: Fosphenytoin
Q12. Which statement best describes a bioprecursor prodrug?
- A prodrug that undergoes metabolic transformation without an added promoiety to form the active drug
- A prodrug that always uses a phosphate promoiety
- A prodrug that cannot be activated enzymatically
- A prodrug that only releases inactive metabolites
Correct Answer: A prodrug that undergoes metabolic transformation without an added promoiety to form the active drug
Q13. Which chemical bond type is commonly used to design colon-targeted prodrugs activated by gut bacteria?
- Azo bond (–N=N–)
- Amide bond only
- Ether bond in sugars
- Disulfide bond exclusively
Correct Answer: Azo bond (–N=N–)
Q14. What is a mutual prodrug?
- A prodrug in which two active drugs are covalently linked and released upon activation
- A single drug with two promoieties that are inert
- A prodrug that has no therapeutic activity after release
- A prodrug designed only for topical use
Correct Answer: A prodrug in which two active drugs are covalently linked and released upon activation
Q15. Valacyclovir was developed to improve which property compared to acyclovir?
- Oral bioavailability
- Photostability only
- Topical potency
- Renal excretion rate exclusively
Correct Answer: Oral bioavailability
Q16. Which analytical technique is most useful to quantify prodrug conversion and metabolites in biological samples?
- HPLC-MS/MS
- Simple colorimetry without separation
- Classical melting point analysis
- Viscosity measurement
Correct Answer: HPLC-MS/MS
Q17. Regulatory evaluation of a prodrug must particularly consider which additional safety aspect?
- The safety and toxicity of the promoiety and its metabolites
- Only the manufacturing cost
- The color of the finished product
- Exclusively the active drug’s patent status
Correct Answer: The safety and toxicity of the promoiety and its metabolites
Q18. How can prodrug design reduce local gastrointestinal irritation of acidic drugs?
- By masking the acidic group (e.g., esterification) to prevent local irritation until systemic conversion
- By increasing the acidity further
- By forming insoluble salts that remain in the gut
- By adding bitter-tasting promoieties
Correct Answer: By masking the acidic group (e.g., esterification) to prevent local irritation until systemic conversion
Q19. Oseltamivir is activated to its active metabolite primarily by which enzyme class?
- Hepatic carboxylesterases
- Aminopeptidases in the gut lumen
- CYP3A4 in the intestine only
- DNA polymerases
Correct Answer: Hepatic carboxylesterases
Q20. Which factor most strongly influences the in vivo activation rate of an enzymatically cleaved prodrug?
- Expression and activity of the activating enzyme(s) in the target tissues
- The color of the capsule
- Ambient room temperature only
- Manufacturer’s country
Correct Answer: Expression and activity of the activating enzyme(s) in the target tissues
Q21. For designing prodrugs to cross the blood–brain barrier, which strategy is commonly used?
- Increase lipophilicity or target transporter systems (e.g., LAT1)
- Reduce lipophilicity to zero
- Attach polar sugars only
- Use large protein carriers
Correct Answer: Increase lipophilicity or target transporter systems (e.g., LAT1)
Q22. Which chemical modification is frequently employed to mask polar functional groups and improve membrane permeability?
- Esterification of hydroxyl or carboxyl groups
- Adding inorganic salts
- Attaching heavy metals
- Forming urea derivatives exclusively
Correct Answer: Esterification of hydroxyl or carboxyl groups
Q23. Which promoiety is commonly used to increase aqueous solubility for intravenous prodrugs?
- Phosphate group
- Long alkyl chain
- Cholesterol residue
- Large aromatic ring
Correct Answer: Phosphate group
Q24. Sulfasalazine is an example of a prodrug activated by which mechanism?
- Bacterial azo-reduction in the colon
- Renal dealkylation
- Oxidation by lung enzymes
- Photochemical cleavage in the skin
Correct Answer: Bacterial azo-reduction in the colon
Q25. Which best describes the mutual prodrug approach?
- Two drugs linked covalently that are designed to be released as active moieties
- A drug linked to a metallic ion for imaging only
- A prodrug that cannot be absorbed orally
- Single drug formulated in a suspension
Correct Answer: Two drugs linked covalently that are designed to be released as active moieties
Q26. Which opioid is commonly cited as a prodrug of morphine?
- Codeine
- Fentanyl
- Buprenorphine
- Methadone
Correct Answer: Codeine
Q27. Capecitabine is an oral prodrug that is ultimately converted into which cytotoxic agent preferentially in tumors?
- 5-Fluorouracil (5-FU)
- Cisplatin
- Doxorubicin
- Paclitaxel
Correct Answer: 5-Fluorouracil (5-FU)
Q28. True or False: Prodrug strategies can be used to reduce gastrointestinal irritation of NSAIDs by masking the free carboxylic acid.
- True
- False
- Only in pediatric patients
- Only when given intravenously
Correct Answer: True
Q29. Which dipeptide linker is commonly used in tumor-activated prodrugs and antibody–drug conjugates (ADCs)?
- Valine–citrulline
- Glycine–glycine only
- Proline–proline exclusively
- Alanine–alanine never used
Correct Answer: Valine–citrulline
Q30. Beyond pharmacology, what is a practical commercial advantage of developing a prodrug version of an existing drug?
- It can create new intellectual property/patent opportunities and extend product lifecycle
- It always reduces manufacturing cost to zero
- It eliminates the need for clinical trials entirely
- It forces immediate over-the-counter status
Correct Answer: It can create new intellectual property/patent opportunities and extend product lifecycle
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
Mail- Sachin@pharmacyfreak.com