Prodrug design: rationale and practical considerations MCQs With Answer

Introduction: Prodrug design: rationale and practical considerations MCQs With Answer is a concise, targeted quiz resource for M.Pharm students focusing on the strategic creation and application of prodrugs. This set emphasizes mechanistic understanding, chemical strategies, enzymatic activation, pharmacokinetic optimization and safety/regulatory considerations. Questions span classification (carrier-linked vs bioprecursor), common pro-moieties (esters, phosphates, amino-acid conjugates, ProTides), activation pathways (esterases, CYPs, peptidases), and practical issues such as stability, enzymatic polymorphism, transporter targeting and preclinical evaluation. The MCQs are designed to deepen conceptual insight and prepare students for advanced coursework and research in drug design.

Q1. Which statement best defines a prodrug?

• A pharmacologically inactive or less active compound that is converted in vivo to an active drug
• A toxic metabolite produced by drug metabolism
• An active drug that requires co-administration with a catalyst to function
• A drug formulation designed only to extend shelf life

Correct Answer: A pharmacologically inactive or less active compound that is converted in vivo to an active drug

Q2. Which of the following is a primary rationale for designing a prodrug?

• To permanently change the pharmacophore and lose activity
• To improve undesirable physicochemical or biopharmaceutical properties such as solubility or permeability
• To avoid any metabolic transformation in the body
• To eliminate the need for dose optimization

Correct Answer: To improve undesirable physicochemical or biopharmaceutical properties such as solubility or permeability

Q3. Carrier-linked prodrugs are characterised by which feature?

• They are activated by direct oxidation to the active form without cleavage
• They consist of the active drug covalently bound to a promoiety which is cleaved enzymatically or chemically
• They involve only transient non-covalent association between drug and transporter
• They are exclusively peptides that become active after phosphorylation

Correct Answer: They consist of the active drug covalently bound to a promoiety which is cleaved enzymatically or chemically

Q4. Which pro-moiety is most commonly used to mask carboxylic acids and improve membrane permeability?

• Phosphate esters
• Alkyl or aryl esters
• Sulfates
• N-oxide

Correct Answer: Alkyl or aryl esters

Q5. Valacyclovir is a well-known prodrug. What strategy does it use to increase oral bioavailability of acyclovir?

• Masking as a sulfate to increase lipophilicity
• Amino-acid ester promoiety to utilize intestinal peptide transporters (PEPT1)
• Conjugation with a polymer to prevent absorption
• Formation of a phosphoramidate ProTide

Correct Answer: Amino-acid ester promoiety to utilize intestinal peptide transporters (PEPT1)

Q6. Which enzymatic class is most frequently responsible for cleavage of ester prodrugs in plasma and tissues?

• CYP450 monooxygenases
• Carboxylesterases
• Transglutaminases
• Lipoxygenases

Correct Answer: Carboxylesterases

Q7. Bioprecursor prodrugs differ from carrier-linked prodrugs because:

• They require cleavage of a promoiety by esterases
• The active drug is generated by metabolic transformation of the parent without loss of a separate promoiety
• They always improve solubility by phosphate groups
• They are activated exclusively by intestinal bacteria

Correct Answer: The active drug is generated by metabolic transformation of the parent without loss of a separate promoiety

Q8. Which prodrug example is correctly matched with its activation mechanism?

• Enalapril — phosphate hydrolysis by alkaline phosphatase
• Fosphenytoin — rapid conversion by phosphatases to phenytoin
• Valacyclovir — CYP2D6 O-demethylation to acyclovir
• Clopidogrel — direct nonenzymatic hydrolysis to active thiol

Correct Answer: Fosphenytoin — rapid conversion by phosphatases to phenytoin

Q9. Which design consideration is critical to avoid toxicity from the promoiety?

• Ensuring the promoiety is pharmacologically inert and rapidly eliminated or metabolized to safe products
• Designing the promoiety to be highly lipophilic to remain in tissues
• Using promoieties that generate reactive electrophiles upon cleavage
• Selecting promoieties that form covalent adducts with albumin

Correct Answer: Ensuring the promoiety is pharmacologically inert and rapidly eliminated or metabolized to safe products

Q10. Which of the following is an advantage of phosphate prodrugs (e.g., fosphenytoin)?

• They are highly lipophilic and cross the blood-brain barrier more easily
• They improve aqueous solubility and allow parenteral administration
• They do not require enzymatic activation
• They always reduce dose frequency by slowing clearance

Correct Answer: They improve aqueous solubility and allow parenteral administration

Q11. ProTide prodrugs (phosphoramidate) such as sofosbuvir are designed primarily to:

• Target PEPT1 transporters in the intestine
• Deliver a nucleoside monophosphate intracellularly, bypassing rate-limiting kinase phosphorylation
• Reduce first-pass metabolism by increasing lipophilicity only
• Release nitric oxide as the active moiety

Correct Answer: Deliver a nucleoside monophosphate intracellularly, bypassing rate-limiting kinase phosphorylation

Q12. Which factor can cause variability in prodrug activation between patients?

• Uniform expression of transporters across populations
• Genetic polymorphisms in activating enzymes (e.g., esterases or CYPs)
• Consistent gastric pH among all individuals
• Standardized diet that eliminates all variability

Correct Answer: Genetic polymorphisms in activating enzymes (e.g., esterases or CYPs)

Q13. When designing a prodrug to target intracellular activation in the liver, which strategy is most appropriate?

• Use a promoiety selectively cleaved by ubiquitous plasma esterases
• Incorporate moieties recognized by hepatic uptake transporters (e.g., OATP) or hepatic enzymes
• Design for complete chemical stability in the body
• Attach large polymers to prevent hepatic entry

Correct Answer: Incorporate moieties recognized by hepatic uptake transporters (e.g., OATP) or hepatic enzymes

Q14. Which in vitro assay is most useful to predict enzymatic activation rate of an ester prodrug?

• Human plasma or tissue homogenate incubation measuring parent disappearance and active formation
• Static solubility in organic solvents only
• In vitro photostability under UVA exposure
• Hexane partition coefficient measurements without enzymes

Correct Answer: Human plasma or tissue homogenate incubation measuring parent disappearance and active formation

Q15. Which chemical modification is commonly used to increase aqueous solubility of a lipophilic drug for parenteral use?

• Conversion to a phosphate ester prodrug
• Attachment of a long-chain alkyl ester promoiety
• Formation of a hydrophobic carbamate that resists hydrolysis
• Removal of all ionizable groups to increase neutral fraction

Correct Answer: Conversion to a phosphate ester prodrug

Q16. Which of these is a concern specific to prodrugs that rely on gut microbial enzymes for activation?

• Predictable uniform activation across all individuals
• Inter-individual variability due to differences in microbiome composition and antibiotic use
• Higher probability of activation by plasma carboxylesterases
• Complete avoidance of first-pass metabolism

Correct Answer: Inter-individual variability due to differences in microbiome composition and antibiotic use

Q17. Mutual prodrugs are best described as:

• Prodrugs containing two identical promoieties attached to one drug
• Two drugs joined covalently so that each acts as a promoiety to release the other active moiety
• Prodrugs requiring co-administration of an enzyme to be active
• Prodrugs that are activated only by acidic pH

Correct Answer: Two drugs joined covalently so that each acts as a promoiety to release the other active moiety

Q18. Which computational approach can assist in prodrug design prior to synthesis?

• In silico prediction of promoiety cleavage kinetics, pKa and passive permeability changes
• Random selection of promoieties without property prediction
• Ignoring ADME parameters and focusing only on color of the compound
• Exclusive use of animal data without molecular modeling

Correct Answer: In silico prediction of promoiety cleavage kinetics, pKa and passive permeability changes

Q19. Regulatory evaluation of a prodrug often requires which additional data compared with the parent drug?

• Only the melting point of the prodrug
• Comprehensive toxicology and metabolism data for the promoiety, metabolites and the active drug
• Evidence that the prodrug is inactive in all in vitro systems without metabolism
• Only a single-dose human tolerance without metabolite profiling

Correct Answer: Comprehensive toxicology and metabolism data for the promoiety, metabolites and the active drug

Q20. Which design factor improves the chance that a prodrug will release the active drug at an appropriate rate in vivo?

• Choosing a promoiety whose cleavage is extremely slow and independent of physiological enzymes
• Balancing chemical stability with susceptibility to specific enzymatic cleavage tuned by linker chemistry
• Ensuring the prodrug is completely unstable under room temperature
• Designing the promoiety so it cannot be recognized by any human enzyme

Correct Answer: Balancing chemical stability with susceptibility to specific enzymatic cleavage tuned by linker chemistry

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