Pharmacogenetics: prodrug activation: practice question

A Pharmacology question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Pharmacology · Pharmacogenetics: prodrug activation

Sample item

A 60-year-old man on clopidogrel after coronary stenting develops stent thrombosis. Genotyping shows CYP2C19*2/*2. What is the likely mechanism of drug failure?

AReduced conversion of the prodrug to its active thiol metaboliteBAccelerated glucuronidation of the active drugCReduced absorption through increased P-glycoprotein expressionDDirect antagonism at the P2Y12 receptor by a metabolite

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

A. Reduced conversion of the prodrug to its active thiol metabolite

Clopidogrel is a prodrug that needs two oxidative steps, mainly by CYP2C19, to generate the active metabolite that irreversibly blocks P2Y12. Poor metabolisers form little active drug and have reduced platelet inhibition and more stent thrombosis. Ticagrelor does not require this activation.

Option by option

A. Reduced conversion of the prodrug to its active thiol metabolite (correct)
Correct. Loss-of-function CYP2C19 alleles reduce the generation of the active metabolite.
B. Accelerated glucuronidation of the active drug
Glucuronidation is not the problem here; the issue is failed activation.
C. Reduced absorption through increased P-glycoprotein expression
Absorption is not the genetic defect described; the genotype affects CYP2C19.
D. Direct antagonism at the P2Y12 receptor by a metabolite
The active metabolite is the P2Y12 blocker; a metabolite does not antagonise its action.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

Questions about this Pharmacology question

What is the answer to this Pharmacology question?

The best answer is A, Reduced conversion of the prodrug to its active thiol metabolite. Clopidogrel is a prodrug that needs two oxidative steps, mainly by CYP2C19, to generate the active metabolite that irreversibly blocks P2Y12.

Why is "Accelerated glucuronidation of the active drug" not the answer?

Glucuronidation is not the problem here; the issue is failed activation.

Why is "Reduced absorption through increased P-glycoprotein expression" not the answer?

Absorption is not the genetic defect described; the genotype affects CYP2C19.

Why is "Direct antagonism at the P2Y12 receptor by a metabolite" not the answer?

The active metabolite is the P2Y12 blocker; a metabolite does not antagonise its action.

What concept does this question test?

It tests Pharmacogenetics: prodrug activation in Pharmacology. Poor metabolisers form little active drug and have reduced platelet inhibition and more stent thrombosis. Ticagrelor does not require this activation.

How hard is this question?

We tag it as an application question: it asks you to use a fact on a patient or a finding. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Pharmacogenetics: prodrug activation?

Learn drugs as classes, then the exception in each class that an examiner would pick. Then use the flashcards and the other Pharmacology questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.