Aspirin in low doses selectively inhibits platelet COX-1 more durably than endothelial COX-2. Which pharmacokinetic property explains this selectivity?

• A Low-dose aspirin achieves higher concentrations in portal blood where platelets are first exposed
• B Low-dose aspirin preferentially acetylates Ser530 on COX-1 but not the equivalent serine on COX-2
• C Platelets are anucleate and cannot synthesize new COX-1 protein; endothelial cells resynthesise COX-2 within hours, restoring prostacyclin production ✓
• D Aspirin is rapidly deacetylated in systemic circulation, exposing only portal blood platelets to the active form

Explanation

Aspirin irreversibly acetylates COX-1 (at Ser530) and COX-2 in all cells. The antiplatelet selectivity of low-dose aspirin (75–100 mg) exploits the fact that platelets are anucleate cells that cannot synthesize new proteins — once their COX-1 is acetylated, it remains inhibited for the platelet's entire lifespan (8–10 days). Endothelial cells, being nucleated, resynthesize COX-2 within 4–8 hours and restore prostacyclin (PGI2) production, which protects against thrombosis. This pharmacodynamic asymmetry allows aspirin to shift the thromboxane A2 (TXA2)/prostacyclin balance toward anti-aggregation at low doses.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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