3.1- Pharmacology
Azithromycin is an antibiotic that belongs to the macrolide family used
in a wide variety of bacterial diseases (respiratory tract infections,
sexually transmitted diseases, etc.)[7]. Its antibacterial mechanism
of action consists of the inhibition of the protein synthesis by
interfering with the assembly of the 50S ribosomal subunit[7].
Azithromycin can be given either 500 mg once daily (OD) for 3-5 days or
500 mg on day 1 followed by 250 mg OD on days 2-5[21].
Although a 37 % of oral bioavailability has been described, the
extensive tissue accumulation offsets its sub-optimal absorption[7].
Its plasma protein binding is 30 %, with a large volume of distribution
of 23-30 L/kg, mainly due to the confinement in intracellular
compartments[7,22]. Azithromycin accumulates in epithelial cells,
fibroblasts, lymphocytes and alveolar macrophages where, compared to
serum, 400 to 1,000-fold higher concentrations can be achieved[7].
This accumulation is due to its dibasic nature (pKa18.1;pKa2 8.8), which in acidic environments as
intracellular lysosomes causes the protonation and trapping into the
cells[23]. The ability to bind to negatively charged phospholipids
in its protonated form further increases this accumulation[23]. The
chemotactic drug delivery increases local drug concentrations, as blood
phagocytes and other cells that migrate into infected and inflamed
tissues release accumulated azithromycin[7,23]. As a consequence,
azithromycin presents a long half-life of 68-79h.[23]
All these properties explain its excellent lung tissue penetration and
sustained drug concentrations[7,21,23]. Following 500 mg OD for
three days, a Cmax of 0.72-0.83 µg/mL in bronchial
washing and 8.93-9.13 µg/mL in lung tissue, compared to 0.18 µg/mL in
plasma, was found[21,24]. After a single oral dose of 500 mg, peak
concentrations were 1.2-2.18 µg/mL in the epithelial lining fluid and
194 µg/mL in alveolar macrophages[22,25]. Finally, azithromycin is
mainly excreted unchanged in feces[7].