Genetic polymorphism in drug transport and targets MCQs With Answer

Introduction: Genetic polymorphism in drug transport and targets MCQs With Answer is designed for M.Pharm students specializing in Clinical Pharmacokinetics and Therapeutic Drug Monitoring. This set of questions explores how inherited variations in membrane transporters and pharmacological targets influence drug absorption, distribution, clearance, efficacy, and adverse effects. Topics covered include ABC and SLC transporter families, receptor polymorphisms, copy number variations, clinically relevant alleles (e.g., SLCO1B1, ABCB1, SLC22A1), genotype-guided dosing, and implications for therapeutic drug monitoring. Questions emphasise mechanistic understanding and clinical application to prepare students for advanced coursework, examinations, and patient-centered pharmacotherapy decisions.

Q1. Which of the following best describes a loss-of-function polymorphism in a drug transporter?

• Allele that increases transporter-mediated drug uptake leading to higher clearance
• Allele that reduces or abolishes transporter protein activity, decreasing substrate uptake or efflux
• Variant that only affects transporter transcription but not protein function
• Polymorphism that causes novel substrate specificity without changing activity level

Correct Answer: Allele that reduces or abolishes transporter protein activity, decreasing substrate uptake or efflux

Q2. SLCO1B1*5 (c.521T>C) polymorphism is clinically important because it is associated with:

• Increased hepatic uptake of statins and reduced systemic exposure
• Decreased hepatic uptake of statins and increased risk of statin-induced myopathy
• Enhanced biliary excretion of statins leading to therapeutic failure
• No clinically relevant change in statin pharmacokinetics

Correct Answer: Decreased hepatic uptake of statins and increased risk of statin-induced myopathy

Q3. Which transporter is primarily responsible for limiting brain penetration of many drugs by efflux at the blood–brain barrier?

• OATP1B1 (SLCO1B1)
• P-glycoprotein (ABCB1)
• OCT1 (SLC22A1)
• MATE1 (SLC47A1)

Correct Answer: P-glycoprotein (ABCB1)

Q4. A patient with homozygous gene deletion of CYP2D6 may display which phenotype relevant to drugs that are CYP2D6 substrates?

• Ultrarapid metabolizer with increased clearance
• Poor metabolizer with reduced drug clearance and possible toxicity
• Intermediate metabolizer with enhanced therapeutic effect
• No change in metabolism because copy number affects only transporters

Correct Answer: Poor metabolizer with reduced drug clearance and possible toxicity

Q5. Which SLC transporter polymorphism is most directly implicated in altered hepatic uptake of methotrexate and some statins?

• SLCO1B1 (OATP1B1)
• SLC22A2 (OCT2)
• ABCB1 (P-glycoprotein)
• SLC47A1 (MATE1)

Correct Answer: SLCO1B1 (OATP1B1)

Q6. How can transporter polymorphisms alter the volume of distribution (Vd) of a drug?

• By altering renal filtration coefficient only
• By changing tissue uptake or efflux, modifying tissue-to-plasma partitioning
• By exclusively affecting plasma protein binding without tissue effects
• They do not affect Vd, only clearance

Correct Answer: By changing tissue uptake or efflux, modifying tissue-to-plasma partitioning

Q7. OCT1 (SLC22A1) loss-of-function variants commonly affect which orally administered drug’s hepatic uptake and glycaemic response?

• Metformin
• Warfarin
• Simvastatin
• Amiodarone

Correct Answer: Metformin

Q8. Which HLA allele is strongly associated with abacavir hypersensitivity and is therefore recommended to be screened prior to therapy?

• HLA-B*57:01
• HLA-B*15:02
• HLA-A*02:01
• HLA-B*27:05

Correct Answer: HLA-B*57:01

Q9. A gain-of-function duplication of CYP2D6 gene copies can lead to which clinical phenotype?

• Poor metabolizer resulting in drug accumulation
• Ultrarapid metabolizer with faster conversion of prodrugs to active metabolites
• Loss of enzymatic activity due to gene dosage imbalance
• No phenotypic consequence because duplicates are nonfunctional

Correct Answer: Ultrarapid metabolizer with faster conversion of prodrugs to active metabolites

Q10. Which polymorphism in the warfarin target gene primarily determines warfarin dose requirement due to altered target sensitivity?

• CYP2C9*3
• VKORC1 -1639G>A
• SLCO1B1*5
• ABCB1 C3435T

Correct Answer: VKORC1 -1639G>A

Q11. In therapeutic drug monitoring, why is knowledge of transporter genotype useful in addition to measuring plasma concentrations?

• Genotype predicts only future concentration but not tissue exposure
• Transporter genotype can explain atypical distribution or unexpected clearance despite normal plasma levels
• Genotyping replaces the need for any TDM measurements
• Transporters only affect oral bioavailability and are irrelevant after IV dosing

Correct Answer: Transporter genotype can explain atypical distribution or unexpected clearance despite normal plasma levels

Q12. ABCB1 C3435T polymorphism has been associated with variability in pharmacokinetics of which type of drugs?

• Small hydrophilic drugs exclusively handled by renal filtration
• Many lipophilic substrates including anticancer agents, antiepileptics and digoxin
• All drugs metabolized by CYP3A4 only
• Vitamins and large peptides that do not cross membranes

Correct Answer: Many lipophilic substrates including anticancer agents, antiepileptics and digoxin

Q13. Which genetic mechanism explains inter-individual differences in transporter expression due to promoter variants or transcription factor binding site changes?

• Copy number variation only
• Regulatory SNPs affecting transcriptional activity
• Nonsense mutations in coding exons exclusively
• Mitochondrial DNA polymorphisms

Correct Answer: Regulatory SNPs affecting transcriptional activity

Q14. The SLC22A2 (OCT2) transporter polymorphism most directly impacts clearance of which agent and its nephrotoxicity risk?

• Cisplatin
• Warfarin
• Fluoxetine
• Atorvastatin

Correct Answer: Cisplatin

Q15. Which statement about pharmacodynamic target polymorphisms is correct?

• They only affect drug metabolism rates, not drug response
• They can change receptor affinity or downstream signaling altering drug efficacy or toxicity
• They are irrelevant when therapeutic drug monitoring is used
• They uniformly increase drug response across all drug classes

Correct Answer: They can change receptor affinity or downstream signaling altering drug efficacy or toxicity

Q16. NUDT15 variants are clinically important because they predispose to severe toxicity with which class of drugs?

• Beta-blockers
• Thiopurines (e.g., azathioprine, 6-mercaptopurine)
• Statins
• Proton pump inhibitors

Correct Answer: Thiopurines (e.g., azathioprine, 6-mercaptopurine)

Q17. Which laboratory approach is commonly used to phenotype transporter activity in vivo for correlation with genotype?

• Urinary excretion of stable isotope-labeled probe substrates
• Complete genome sequencing without functional tests
• Measuring total cholesterol as an indirect index
• Electrocardiography to assess transporter function

Correct Answer: Urinary excretion of stable isotope-labeled probe substrates

Q18. A patient carrying loss-of-function alleles in both SLCO1B1 and ABCG2 transporters may experience which combined effect on oral statin therapy?

• Decreased systemic exposure and reduced adverse effect risk
• Increased systemic exposure and higher risk of myopathy due to reduced hepatic uptake and reduced efflux
• No change in statin pharmacokinetics because transporters compensate perfectly
• Exclusive increase in renal clearance with no hepatic impact

Correct Answer: Increased systemic exposure and higher risk of myopathy due to reduced hepatic uptake and reduced efflux

Q19. Which clinical action is most appropriate when a patient is identified as an ultrarapid metabolizer for a prodrug activated by CYP2D6?

• Reduce the prodrug dose because of risk of accumulation of parent compound
• Expect higher-than-normal levels of active metabolite and monitor for exaggerated effects or toxicity
• Switch to a drug that is a CYP2D6 substrate to exploit faster metabolism
• No monitoring is necessary because ultrarapid metabolism always reduces efficacy

Correct Answer: Expect higher-than-normal levels of active metabolite and monitor for exaggerated effects or toxicity

Q20. Which concept explains why the same transporter polymorphism may have different clinical impact in two drugs that are both substrates?

• All substrates are affected identically by a transporter change
• Substrate-specific affinity, alternative clearance pathways, and therapeutic index modulate clinical impact
• Transporter polymorphisms only matter for intravenously administered drugs
• Population allele frequency is the only determinant of clinical effect

Correct Answer: Substrate-specific affinity, alternative clearance pathways, and therapeutic index modulate clinical impact

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