Examples of genetically determined ADRs affecting pharmacokinetics MCQs With Answer

Genetically determined ADRs affecting pharmacokinetics occur when inherited variations in drug‑metabolizing enzymes, transporters or conjugating proteins alter absorption, distribution, metabolism or excretion, producing unexpected toxicity or therapeutic failure. Key pharmacogenetics keywords for B. Pharm students include CYP450 (CYP2D6, CYP2C9, CYP2C19, CYP3A5), TPMT, NAT2, UGT1A1, SLCO1B1 and DPYD. Clinical examples include codeine toxicity, warfarin bleeding, thiopurine myelosuppression, isoniazid neuropathy, irinotecan neutropenia, statin myopathy and 5‑FU toxicity. Understanding metabolizer phenotypes, transporter effects and when to apply genotyping/phenotyping supports personalized dosing, drug selection and monitoring. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. Which statement best defines genetically determined ADRs that affect pharmacokinetics?

• Genetic variations that alter drug absorption, distribution, metabolism, or excretion leading to adverse drug reactions.
• Immune reactions caused by exposure to foreign proteins in medications.
• Idiosyncratic reactions unrelated to drug concentrations.
• Only HLA‑mediated hypersensitivity reactions.

Correct Answer: Genetic variations that alter drug absorption, distribution, metabolism, or excretion leading to adverse drug reactions.

Q2. A patient with CYP2D6 ultra‑rapid metabolizer genotype takes codeine. What is the most likely pharmacokinetic consequence?

• Reduced conversion of codeine to morphine and therapeutic failure.
• Increased conversion of codeine to morphine and risk of opioid toxicity.
• No change in metabolism or risk profile.
• Increased renal excretion of codeine leading to lower effect.

Correct Answer: Increased conversion of codeine to morphine and risk of opioid toxicity.

Q3. CYP2C9 loss‑of‑function variants (e.g., *2, *3) primarily cause which effect on warfarin therapy?

• Faster clearance and reduced anticoagulant effect.
• No change in warfarin pharmacokinetics.
• Slower metabolism leading to higher warfarin levels and increased bleeding risk.
• Increased activation of warfarin prodrug to active form.

Correct Answer: Slower metabolism leading to higher warfarin levels and increased bleeding risk.

Q4. Thiopurine S‑methyltransferase (TPMT) deficiency predisposes patients to which toxicity when given azathioprine or mercaptopurine?

• Hepatotoxicity without bone marrow effects.
• Severe myelosuppression due to accumulation of thioguanine nucleotides.
• Renal failure from drug precipitation.
• Peripheral neuropathy through demyelination.

Correct Answer: Severe myelosuppression due to accumulation of thioguanine nucleotides.

Q5. Slow acetylator phenotype of NAT2 increases risk of which adverse effect with isoniazid?

• Enhanced prodrug activation and therapeutic failure.
• Peripheral neuropathy and hepatotoxicity due to higher isoniazid exposure.
• Decreased absorption and cough persistence.
• Renal calculi due to metabolite accumulation.

Correct Answer: Peripheral neuropathy and hepatotoxicity due to higher isoniazid exposure.

Q6. UGT1A1*28 polymorphism is clinically important because it increases risk of toxicity with which anticancer drug?

• 5‑Fluorouracil.
• Irinotecan (due to impaired glucuronidation of SN‑38).
• Cisplatin.
• Vincristine.

Correct Answer: Irinotecan (due to impaired glucuronidation of SN‑38).

Q7. A common SLCO1B1 (OATP1B1) c.521T>C variant increases risk of which ADR with simvastatin?

• Hepatotoxicity without muscle symptoms.
• Statin‑associated myopathy due to reduced hepatic uptake and higher plasma levels.
• Hyperglycemia from altered metabolism.
• QT prolongation via hERG inhibition.

Correct Answer: Statin‑associated myopathy due to reduced hepatic uptake and higher plasma levels.

Q8. DPYD (dihydropyrimidine dehydrogenase) deficiency most directly affects pharmacokinetics of which drug class?

• Beta‑lactam antibiotics.
• Fluoropyrimidines such as 5‑fluorouracil and capecitabine, increasing severe toxicity.
• Nonsteroidal anti‑inflammatory drugs causing GI bleeding.
• Statins causing muscle symptoms.

Correct Answer: Fluoropyrimidines such as 5‑fluorouracil and capecitabine, increasing severe toxicity.

Q9. How does a CYP3A5 expresser genotype affect tacrolimus dosing?

• No effect on tacrolimus pharmacokinetics.
• Expressers (e.g., *1 allele) metabolize tacrolimus faster and often require higher doses.
• Expressers require significantly lower doses due to accumulation.
• Expressers convert tacrolimus to an inactive prodrug.

Correct Answer: Expressers (e.g., *1 allele) metabolize tacrolimus faster and often require higher doses.

Q10. ABCB1 (P‑glycoprotein) polymorphisms can alter blood levels of which narrow‑therapeutic‑index drug?

• Digoxin, by changing intestinal absorption and renal elimination.
• Ibuprofen, by altering COX inhibition.
• Paracetamol, by changing hepatic glucuronidation only.
• Metformin, through increased hepatic metabolism.

Correct Answer: Digoxin, by changing intestinal absorption and renal elimination.

Q11. Loss‑of‑function CYP2C19 alleles reduce activation of which prodrug, increasing risk of cardiovascular events?

• Clopidogrel.
• Aspirin.
• Atorvastatin.
• Heparin.

Correct Answer: Clopidogrel.

Q12. Which metabolite accumulates in TPMT deficiency causing myelosuppression?

• 6‑Methylmercaptopurine (inactive metabolite).
• 6‑Thioguanine nucleotides.
• 6‑Oxopurine.
• Thymidine triphosphate.

Correct Answer: 6‑Thioguanine nucleotides.

Q13. How do loss‑of‑function variants in enzymes that activate prodrugs typically affect therapy?

• They increase formation of the active drug and toxicity.
• They reduce formation of active metabolite causing therapeutic failure.
• They have no effect on prodrug activation.
• They convert prodrugs to alternative active metabolites improving efficacy.

Correct Answer: They reduce formation of active metabolite causing therapeutic failure.

Q14. Ultra‑rapid metabolizers of an active drug generally show which pharmacokinetic pattern?

• Increased plasma half‑life and risk of toxicity.
• Faster clearance leading to lower plasma concentrations and potential therapeutic failure.
• No change in drug exposure compared with extensive metabolizers.
• Accumulation due to impaired renal excretion.

Correct Answer: Faster clearance leading to lower plasma concentrations and potential therapeutic failure.

Q15. SLCO1B1 variants primarily affect which pharmacokinetic process for statins?

• Renal tubular secretion of statins.
• Intestinal absorption of statins.
• Hepatic uptake of statins reducing clearance and increasing plasma levels.
• Phase I oxidative metabolism by CYP450 enzymes.

Correct Answer: Hepatic uptake of statins reducing clearance and increasing plasma levels.

Q16. Which population has a relatively high frequency of CYP2D6 ultra‑rapid metabolizers?

• East Asians (e.g., Japanese and Chinese) predominantly.
• North Africans and some Middle Eastern populations (including Ethiopians).
• Northern Europeans exclusively.
• Native Americans only.

Correct Answer: North Africans and some Middle Eastern populations (including Ethiopians).

Q17. A patient who is a CYP2C19 poor metabolizer after PCI on clopidogrel is at risk of thrombosis. What is the best pharmacotherapy change?

• Decrease clopidogrel dose and continue monitoring.
• Switch to prasugrel or ticagrelor which do not require CYP2C19 activation.
• Add a CYP2C19 inducer to increase activation.
• Replace clopidogrel with aspirin monotherapy only.

Correct Answer: Switch to prasugrel or ticagrelor which do not require CYP2C19 activation.

Q18. What is the primary enzymatic function of UGT1A1 relevant to drug pharmacokinetics?

• N‑acetylation of hydrazine drugs.
• Glucuronidation (conjugation) of bilirubin and drug metabolites, increasing water solubility for excretion.
• Oxidation by cytochrome P450 only.
• Active tubular secretion in the kidney.

Correct Answer: Glucuronidation (conjugation) of bilirubin and drug metabolites, increasing water solubility for excretion.

Q19. Which drug dose must be carefully reduced or avoided in patients with DPYD loss‑of‑function variants?

• Metformin.
• 5‑Fluorouracil (5‑FU) and capecitabine.
• Amoxicillin.
• Warfarin.

Correct Answer: 5‑Fluorouracil (5‑FU) and capecitabine.

Q20. The SLCO1B1 c.521T>C allele is associated with increased systemic exposure to which statin most commonly linked to myopathy in studies?

• Rosuvastatin.
• Simvastatin, especially its active acid form.
• Pravastatin with no myopathy risk.
• Fluvastatin only when combined with fibrates.

Correct Answer: Simvastatin, especially its active acid form.

Q21. What is the likely outcome when a CYP inhibitor drug is given to a patient who is also a genetic poor metabolizer for the same CYP enzyme?

• Effects cancel out and return to normal metabolism.
• Marked increase in parent drug levels and risk of severe toxicity due to additive inhibition.
• Decrease in drug exposure due to enzyme induction.
• Only pharmacodynamic effects change, not pharmacokinetics.

Correct Answer: Marked increase in parent drug levels and risk of severe toxicity due to additive inhibition.

Q22. NAT2 slow acetylator status is associated with increased risk of which drug‑related adverse effect besides isoniazid neuropathy?

• Increased clearance of sulfonamides leading to therapeutic failure.
• Hydralazine or procainamide‑induced lupus due to slow acetylation and higher exposure.
• Increased glucuronidation of bilirubin.
• Reduced anticoagulant effect of warfarin.

Correct Answer: Hydralazine or procainamide‑induced lupus due to slow acetylation and higher exposure.

Q23. Which diagnostic approach can identify patients at risk for severe 5‑FU toxicity due to DPYD variants?

• Measure serum creatinine clearance only.
• DPYD genotyping or measurement of elevated plasma uracil/dihydrouracil ratio.
• Test for TPMT activity instead.
• Urine drug screen for 5‑FU metabolites only after toxicity occurs.

Correct Answer: DPYD genotyping or measurement of elevated plasma uracil/dihydrouracil ratio.

Q24. What is the recommended action for a known CYP2D6 ultra‑rapid metabolizer prescribed codeine for pain?

• Increase the codeine dose for better pain control.
• Avoid codeine and use an alternative analgesic not dependent on CYP2D6 activation.
• Prescribe a CYP2D6 inhibitor to slow metabolism.
• No change; monitor for usual adverse effects only.

Correct Answer: Avoid codeine and use an alternative analgesic not dependent on CYP2D6 activation.

Q25. UGT1A1*28 allele carriers may show exaggerated hyperbilirubinemia when treated with which HIV drug that inhibits UGT1A1?

• Zidovudine.
• Atazanavir.
• Efavirenz.
• Lamivudine.

Correct Answer: Atazanavir.

Q26. A duplicated active CYP2D6 gene copy results in which molecular effect?

• Loss‑of‑function leading to poor metabolism.
• Gene duplication causing gain‑of‑function and ultrarapid metabolism.
• No change in enzyme activity.
• Switch from phase I to phase II metabolism exclusively.

Correct Answer: Gene duplication causing gain‑of‑function and ultrarapid metabolism.

Q27. In which clinical area is pre‑treatment pharmacogenetic testing for TPMT, DPYD and UGT1A1 most commonly applied?

• Dermatology for topical steroids.
• Oncology and chemotherapy to reduce severe drug toxicity.
• Pain management for opioid rotation only.
• Vaccinology for adjuvant response prediction.

Correct Answer: Oncology and chemotherapy to reduce severe drug toxicity.

Q28. Reduced function of SLCO1B1 will most likely cause which change in statin pharmacokinetics?

• Lower plasma statin concentration and reduced efficacy.
• Higher plasma statin concentration and increased risk of myopathy.
• No change because statins are only renally excreted.
• Increased first‑pass metabolism by CYP3A4.

Correct Answer: Higher plasma statin concentration and increased risk of myopathy.

Q29. Which genetic tests are most useful to guide initial warfarin dosing to reduce bleeding risk?

• Genotyping for CYP2C9 and VKORC1 variants alongside clinical factors.
• Testing for TPMT and DPYD variants only.
• HLA‑B*15:02 screening exclusively.
• SLCO1B1 genotyping only.

Correct Answer: Genotyping for CYP2C9 and VKORC1 variants alongside clinical factors.

Q30. Which transporter gene polymorphism has been implicated in altered methotrexate disposition and toxicity?

• SLCO1B1 (OATP1B1), affecting hepatic uptake of methotrexate.
• CYP2D6, which directly metabolizes methotrexate.
• UGT1A1 only, via glucuronidation of methotrexate.
• VKORC1, influencing methotrexate anticoagulant effects.

Correct Answer: SLCO1B1 (OATP1B1), affecting hepatic uptake of methotrexate.

Download