Abstract
The effect of various compounds on the gastric emptying rate of a non-absorbable marker (14C-polyethylene glycol) in the rat has been studied. A correlation between gastric emptying rate and anticholinergic activity has been observed. It is postulated that compounds with anticholinergic activity delay gastric emptying as a result of this activity. Imipramine, a compound found to be a potent inhibitor of gastric emptying, has been used to delay gastric emptying in studies of the intestinal absorption of drugs in the rat. Absorption has been assessed by examination of the plasma level profile of radioactivity and by fitting plasma radioactivity levels, resulting from labelled drug, to a single compartment open model. Delayed gastric emptying has been found to reduce the rate of absorption of trimethoprim in both fed and starved rats. The results indicate that, when reduced, gastric emptying rate becomes the rate limiting step in absorption. The rate of absorption of trimethoprim has also been found to be more rapid in fed than in starved rats. A slower rate of intestinal motility is suggested as the reason for this finding. The rate of absorption in starved rats of salicylic acid was also found to be reduced by delayed gastric emptying. The results indicated that when emptying is delayed gastric absorption of salicylate contributes significantly to its overall rate of intestinal absorption. Imipramine has also been shown to increase the amount of both salicylic acid and trimethoprim absorbed via intestinal lymph. A novel mathematical model has been proposed to describe intestinal transit in the rat. Using this model the rate of intestinal transit has been shown to be rapid near the stomach and to decrease exponentially as the distance along the intestine increases. Transit rate was found to be slower in fed animals. Imipramine pretreatment caused a decrease in the rate of transit in both fed and starved animals. An experiment is described which was designed to investigate the effects of some anticholinergic compounds on the absorption of salicylic acid in human volunteers. Suggestions are made as to the relevance of the results presented in relation to investigations of toxicology and metabolism of drugs. The possible consequences of alterations in gastric emptying caused by the administration of therapeutic agents to humans are discussed. In particular potential adverse drug interactions and toxic side-effects are indicated.