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

Abstract

BACKGROUND AND PURPOSEThe 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. EXPERIMENTAL APPROACH[ 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. KEY RESULTSAzithromycin (1-100 mM) and erythromycin (3-30 mM) concentration-dependently displaced [ 125 I]-motilin binding to the motilin receptor (52 Ϯ 7 and 58 Ϯ 18% displacement at 100 and 30 mM 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 mM (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 mM each) facilitated these contractions (apparent Emax values of 2007 Ϯ 396 and 1924 Ϯ 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. CONCLUSIONS AND IMPLICATIONSAzithromcyin 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. AbbreviationsCHO-K1, CHO type K1 cells; EC50, concentration which provides a response equal to 50% of the maximum; EFS, electrical field stimulation; Emax, maximum response to agonist; GI, gastrointestinal; MMC, migrating motor complex

Untitled

“…19 Despite the controversy of the cellular mechanism of prokinetic & other effects of erythromycin on various parts of the gastrointestinal tract in different species, the prokinetic effect of erythromycin is confirmed beyond doubt in humans. [4][5][6][7][8][9][10][11][12][13] In conclusion, the present study shows that erythromycin base has different effects on different parts of the gastrointestinal tract in different species of animals in vitro. The cellular mechanism of effects of erythromycin on various parts of gastrointestinal tract is still not known with certainty.…”

“…15 It has been shown that erythromycin interacts directly with the motilin receptor and exerts agonistic action and also causes stimulation of the cholinergic system which may be responsible for its effects on gastrointestinal motility. 12,14 In animal experiments conducted both in vitro and in vivo, equivocal findings have been reported hence in the present study qualitative effect of erythromycin was studied on isolated rat colon, guinea pig ileum and rhythmically contracting rabbit jejunum.…”

“…[4][5][6][7][8] Acute and chronic treatment with erythromycin improves gastric emptying in idiopathic and diabetic gastroparesis 9,10 as well as post vagotomy gastroparesis. 11 It increases the tone of lower oesophageal sphincter and relieves dyspeptic symptoms in patients with gastrooesophageal reflux disease 12,13 and also stimulates gall bladder emptying. 14 Erythromycin has shown variable responses in animal studies.…”

Azithromycin in Early Infancy and Pyloric Stenosis

“…The median (IQR) age for infants prescribed erythromycin and azithromycin was 49 days (23-70) and 68 days (50-80; P , .001), respectively. The median number of days after exposure to erythromycin in which the 17 infants underwent pyloromyotomy was 13 days (range, 2-40; IQR, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. The median number of days between exposure to azithromycin in the 8 infants and subsequent pyloromyotomy was longer than the interval for the erythromycin group at 29.5 days (range, 9-45; IQR 20.5-38.5; P = .08).…”

“…14,15 Similarly, azithromycin acts as a motilin receptor agonist and causes long-lasting facilitation of cholinergic activity in experiments by using circular muscle of human gastric antrum. 16 Azithromycin has also been shown to stimulate antral activity and induce migrating motor complexes in the duodenum in patients with gastrointestinal dysmotility. 17,18 Our study has several limitations.…”