The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin

The antibiotic azithromycin is a suggested alternative to erythromycin for treating patients with delayed gastric emptying. However, although hypothesized to activate motilin receptors, supportive evidence is unavailable. This was investigated using recombinant and naturally expressed motilin receptors in human stomach, comparing azithromycin with erythromycin.

[(125)I]-motilin binding and calcium flux experiments were conducted using human recombinant motilin receptors in CHO cells. Neuromuscular activities were studied using circular muscle of human gastric antrum, after electrical field stimulation (EFS) of intrinsic nerves.

Azithromycin (1-100 microM) and erythromycin (3-30 microM) concentration-dependently displaced [(125)I]-motilin binding to the motilin receptor (52 ± 7 and 58 ± 18% displacement at 100 and 30 microM respectively). Azithromycin, erythromycin and motilin concentration-dependently caused short-lived increases in intracellular [Ca(2+)] in cells expressing the motilin receptor. EC50 values were, respectively, 2.9, 0.92 and 0.036 microM (n = 3 each); and maximal activities were similar. In human stomach, EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. Azithromycin and erythromycin lactobionate (30-300 microM each) facilitated these contractions (apparent E(max) values of 2007 ± 396 and 1924 ± 1375%, n = 3-4 each concentration, respectively). These actions were slow in onset and faded slowly. The higher concentrations also evoked short-lived muscle contraction. Contractions to a submaximally effective concentration of carbachol were unaffected by either drug.

Azithromcyin activates human recombinant motilin receptors in therapeutically relevant concentrations, similar to erythromycin. In humans, gastric antrum azithromycin caused long-lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic activity of azithromycin.