Effects of a new motilide, ABT‐229, on gastric emptying and postprandial antroduodenal motility in healthy volunteers

Abstract

Since 1984 many studies have described the effects of the macrolide antibiotic erythromycin on gastrointestinal motility. 1±3 Erythromycin was subsequently shown to be an agonist of the motilin receptor. 4 Motilin is a peptide gut hormone, which is produced in the duodenum and plays a role in the regulation of upper gastrointestinal motility. 5 In healthy humans, erythromycin induces contractions of the gastric antrum, enhances antropyloroduodenal co-ordination, induces antral phase III activity and enhances the tone of the gastric fundus. 6±12 In patients with diabetic or postvagotomy gastroparesis, erythromycin stimulates antral motility and normalizes gastric emptying. 3, 13±20 However, a major disadvantage of the use of erythromycin as a prokinetic drug is its antibacterial activity and the risk of inducing a resistant bacterial strain. Therefore, new erythromycin analogues have been developed, so-called motilides, which lack antibiotic activity. One of these, ABT-229 (8,9-anhydro-4¢¢-deoxy-3¢-N-desmethyl-3¢-N-ethylerythromycin B 6,9-hemiacetal), has a relatively high bioavailability after oral administration and strong prokinetic effects in vitro. 21 This study was designed to investigate the effects of two single oral doses (4 mg, 16 mg) of ABT-229 on the SUMMARY Background: ABT-229 is a recently developed derivative of erythromycin, devoid of antibiotic activity. We studied the effect of ABT-229 on gastric emptying and postprandial antroduodenal motility in healthy volunteers. Methods: Placebo, 4 and 16 mg ABT-229 were given as a single oral dose to nine healthy volunteers, in a randomized, 3-period crossover design. A solid meal (250 kcal) was given twice, 45 min after drug ingestion and 4 h later. Gastric emptying of each meal was studied using the 13 C-octanoic breath test. Antroduodenal motility was recorded during the total 9-h period.

Desensitization of the Human Motilin Receptor by Motilides

“…Indeed, when motilin receptors are not present on the cell surface, even endogenous motilin will not be able to induce contractions. The observation that less antral contractions after a second meal occur in healthy volunteers treated with ABT-229 compared with placebo (Verhagen et al, 1997) is consistent with this hypothesis. A down-regulation of motilin receptors has also been shown in rabbits that had been treated with ABT-229 for 4 weeks (Depoortere et al, 1999).…”

“…Internalization of the motilin receptor might explain why the high blood levels of ABT-229 were not able to induce gastric contractions and, hence, accelerate gastric emptying of a second meal in healthy subjects (Verhagen et al, 1997). However, the effects of ABT-229 have not just been described as nonexistent; moreover a worsening of symptoms has been reported by patients with functional dyspepsia (Talley et al, 2000) and diabetic gastroparesis (Talley et al, 2001).…”

“…Tachyphylaxis was also observed after treatment of healthy subjects with ABT-229. A single dose of ABT-229 increased gastric emptying after the first meal, but emptying of a second meal was not affected, although ABT-229 plasma levels were still high (Verhagen et al, 1997).…”

Characterization of Agonist-Induced Motilin Receptor Trafficking and Its Implications for Tachyphylaxis

“…It is possible that MR tachyphylaxis was the primary cause for lack of efficacy, although gastroparesis clinical trials have been criticized for their small sample sizes, uncontrolled designs, short duration, and inadequate symptom assessment (Tack and Peeters, 2001;Camilleri, 2002;Maganti et al, 2003). Clinical data show that a single dose of ABT-229 strongly increased gastric emptying after the first meal in healthy volunteers, but no effect was observed after the second meal despite the presence of considerable residual drug concentrations in the serum (Verhagen et al, 1997). Such clinical evidence of functional motilin receptor desensitization has been reproduced in cell cultures using ABT-229 and other agonists (Li et al, 2004).…”

Effects of Nitric Oxide Synthase Inhibitor on the Digestive System Measured by Simultaneous Monitoring of Gastric Motility, Gastric Emptying Activity and Postprandial Pancreaticobiliary Secretion in Dogs

“…Indeed, cisapride (a 5-HT 4 receptor agonist) and EM574 (a motilin agonist, an erythromycin derivative) enhance the postprandial contractile activity of the gastric antrum and accelerate gastric emptying in dogs [36] and humans [4]. Recently, ABT229, which is a novel motilide and a more potent synthetic derivative of eryth- romycin without antibiotic activity, has been investigated as a potential prokinetic drug which stimulates gastrointestinal motor activity via activation of motilin receptors [5] and accelerates gastric emptying [6,41].…”