Effects of fedotozine on gastrointestinal motility in dogs: mechanism of action and related pharmacokinetics.

The effects of fedotozine, (+)-(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N-dim eth yl- n-propylamine, on motility of the antrum and small intestine were investigated in dog. In fasted dogs, following i.v. administration, fedotozine at 1 and 2 mg kg-1 stimulated and at 5 mg kg-1 inhibited antral motility. Between 1 to 5 mg kg-1, fedotozine exhibited a sustained and potent stimulatory effect on the small intestine inducing 1 to 4 phases III of the migrating motor complex (MMC) lasting up to 32 min in the duodenum and migrating to the jejunum. Following oral administration, fedotozine at 2.5 and 5 mg kg-1 constantly stimulated both antrum and small intestinal motility. In fed dogs, fedotozine i.v. (2 mg kg-1) increased antral motility and induced phase III of MMC in the place of postprandial pattern. Naloxone (0.3 mg kg-1 i.v.) and naloxone methylbromide (2 mg kg-1 i.v.) inhibited the stimulatory effects of fedotozine on gastrointestinal motility indicating a peripheral opiate site of action of the drug whereas phentolamine, hexamethonium, propranolol and methysergide were inactive. In-vitro fedotozine showed submicromolar affinity for opiate receptors with a weak specificity for the mu-receptors in guinea-pig brain and myenteric plexus preparations. Plasma concentrations in dogs receiving fedotozine administered orally at 2.5 mg kg-1 (and in all dogs except one at 5 mg kg-1) were below the detection limit (less than 20 ng g-1). In contrast, tissue concentrations in the muscle and mucosal layers of the gut were above 1 microgram g-1.(ABSTRACT TRUNCATED AT 250 WORDS)