Effects of Motilin and Mitemcinal (GM-611) on Gastrointestinal Contractile Activity in Rhesus Monkeys In Vivo and In Vitro

Abstract

Neither the presence of motilin receptors nor their action has been investigated in monkeys. The object of this study was to determine the effects of motilin and mitemcinal (GM-611), an erythromycin derivative, on the gastrointestinal tract in rhesus monkeys in vivo and in vitro. In in vivo investigations in conscious monkeys, both motilin and mitemcinal induced migrating motor complex-like contractions in the interdigestive state and also accelerated gastric emptying. In in vitro investigations, the presence of motilin receptors in the gastrointestinal tract was demonstrated by receptor binding assays. Motilin and mitemcinal contracted isolated duodenum strips in a concentration-dependent manner. In conclusion, rhesus monkeys may be useful for studying the physiological and pharmacological roles of the motilin agonistic mechanism because they show reactivity to motilin both in vivo and in vitro.

Effects of Oral Mitemcinal (GM-611), Erythromycin, EM-574 and Cisapride on Gastric Emptying in Conscious Rhesus Monkeys

“…Since our earlier study showed that motilin and mitemcinal stimulated gastrointestinal contractions via motilin receptors in monkeys both in vivo and in vitro, as in humans [17], it can be assumed that mitemcinal accelerated gastric emptying in monkeys in the present study because its activity as a motilin agonist increased gastrointestinal contractile activity.…”

“…Our earlier study in Rhesus monkeys established that, unlike other commonly used animals, the in vitro and in vivo responses of Rhesus monkeys to motilin and motilin agonists (including mitemcinal) are similar to those seen in humans [17]. In the present study, therefore, we administered oral mitemcinal and three comparators (erythromycin, EM-574 [18] and cisapride) in conscious Rhesus monkeys and assessed and compared the effects of these drugs on gastric emptying, with the aim of investigating whether the effects of mitemcinal in monkeys would give further support to the hypothesis that mitemcinal has the potential to take the place of cisapride.…”

“…Specifically, in vitro, motilin-specific binding in the smooth muscle layer of upper gastrointestinal tissues was demonstrated in monkeys, as in humans, and both motilin and mitemcinal contracted isolated duodenal strips via motilin receptors in monkeys, as in humans. Furthermore, in vivo, intravenously administered motilin and mitemcinal dose-dependently induced MMC-like gastrointestinal contractions and accelerated gastric emptying in monkeys, as in humans [17]. We therefore judged the Rhesus monkey to be a superior model of the human response to motilin receptor agonists such as mitemcinal.…”

Nonlinear intestinal pharmacokinetics of mitemcinal, the first acid-resistant non-peptide motilin receptor agonist, in rats

“…Mitemcinal has shown potent gastrointestinal motility-stimulating activity via motilin receptors in rabbits, dogs, and monkeys Ozaki et al 2007;Yogo et al 2007). In clinical studies, it has improved delayed gastric emptying (Fang et al 2004) and symptoms (McCallum and Cynshi 2007) in patients with diabetic gastroparesis.…”

Preclinical Electrophysiology Assays of Mitemcinal (Gm-611), a Novel Prokinetic Agent Derived From Erythromycin

“…1.; Koga et al, 1994). Mitemcinal has shown potent gastrointestinal motility-stimulating activity via motilin receptors in rabbits, dogs and monkeys Ozaki et al, 2007;Yogo et al, 2007). Cisapride, a piperidinyl benzamide prokinetic agent used for the treatment of gastrointestinal disorders, was withdrawn from the market in the United States in 2000 because of its propensity to prolong the QT interval, leading to lifethreatening TdP arrhythmias (Wysowski and Bacsanyi, 1996).…”