A 40-year-old man with community-acquired pneumonia is treated with azithromycin. The drug accumulates to high concentrations inside alveolar macrophages and fibroblasts. Which structural feature of azithromycin primarily accounts for this extensive tissue uptake and intracellular accumulation?
- A Active transport by P-glycoprotein into macrophages
- B Its high water solubility and small molecular weight
- C Its 15-membered lactone ring with a tertiary amine (weak base, ion trapping in acidic compartments) ✓
- D Its beta-lactam ring enabling cell wall penetration
Correct answer: C. Its 15-membered lactone ring with a tertiary amine (weak base, ion trapping in acidic compartments)
Explanation
Azithromycin has a weakly basic tertiary amino group (from the nitrogen inserted into the 15-membered macrolide ring) with a pKa of approximately 8.7. This allows ion trapping: in acidic intracellular compartments (lysosomes, pH approximately 5), the drug becomes protonated and cannot cross back out, leading to massive intracellular accumulation (tissue-to-serum ratios of 100:1 to 1000:1). This explains its efficacy against intracellular pathogens like Legionella and Chlamydia. Option D is clearly wrong as azithromycin lacks a beta-lactam ring.
Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.