Molecular biology and genetics: CYP2C19 and clopidogrel: practice question

A Biochemistry 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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Biochemistry · Molecular biology and genetics: CYP2C19 and clopidogrel

Sample item

A patient with a drug-eluting coronary stent on clopidogrel develops stent thrombosis. Genotyping shows two CYP2C19 loss-of-function alleles. Why is the antiplatelet effect reduced?

AIntestinal P-glycoprotein pumps the drug back into the gut lumenBClopidogrel is a prodrug and is poorly converted to its active metaboliteCThe platelet P2Y12 receptor is altered so that the drug cannot bindDThe active metabolite is inactivated too quickly by hepatic glucuronidation

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

The answer and the reasoning

B. Clopidogrel is a prodrug and is poorly converted to its active metabolite

Clopidogrel needs two oxidative steps, mainly by CYP2C19, to form the active thiol metabolite that irreversibly blocks the platelet P2Y12 receptor. Loss-of-function alleles reduce this conversion and platelet inhibition. Ticagrelor and prasugrel do not depend on CYP2C19.

Option by option

A. Intestinal P-glycoprotein pumps the drug back into the gut lumen
P-glycoprotein variation modulates absorption but is not the genotype described.
B. Clopidogrel is a prodrug and is poorly converted to its active metabolite (correct)
Correct. Poor CYP2C19 activation reduces the active metabolite.
C. The platelet P2Y12 receptor is altered so that the drug cannot bind
The receptor is normal in this patient; the problem is activation of the prodrug.
D. The active metabolite is inactivated too quickly by hepatic glucuronidation
Glucuronidation of the active metabolite is not the cause.

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 Biochemistry question

What is the answer to this Biochemistry question?

The best answer is B, Clopidogrel is a prodrug and is poorly converted to its active metabolite. Clopidogrel needs two oxidative steps, mainly by CYP2C19, to form the active thiol metabolite that irreversibly blocks the platelet P2Y12 receptor.

Why is "Intestinal P-glycoprotein pumps the drug back into the gut lumen" not the answer?

P-glycoprotein variation modulates absorption but is not the genotype described.

Why is "The platelet P2Y12 receptor is altered so that the drug cannot bind" not the answer?

The receptor is normal in this patient; the problem is activation of the prodrug.

Why is "The active metabolite is inactivated too quickly by hepatic glucuroni…" not the answer?

Glucuronidation of the active metabolite is not the cause.

What concept does this question test?

It tests Molecular biology and genetics: CYP2C19 and clopidogrel in Biochemistry. Loss-of-function alleles reduce this conversion and platelet inhibition. Ticagrelor and prasugrel do not depend on CYP2C19.

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 Molecular biology and genetics: CYP2C19 and clopidogrel?

Build one table of enzyme deficiency, disease, inheritance and key finding, then revise it by spaced recall. Then use the flashcards and the other Biochemistry 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.