Showing papers by "Gordon L. Amidon published in 1987"

The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon

Abstract: A physiological flow model is presented to account for plasma level double peaks based on cyclical gastric emptying and intestinal motility in the fasted state. Central to the model is the assumption that gastric emptying and intestinal transit rates will vary directly with the strength of the contractile activity characteristic of the fasted state motility cycle. Simulated curves clearly indicate that variable gastric emptying rates can result in variable absorption rates from the gastrointestinal tract and double peaks in the plasma level curves of cimetidine. Vital to the occurrence of double peaks are (i) dosing time relative to phasic activity, (ii) variability in flow out of the stomach, and (iii) a small emptying rate constant Qs/Vs, for a period of time within the first hour after administration. Variability in intestinal flow rates alone does not cause a double peak in the plasma level curve. Results of the simulations, as well as experimental results, can be categorized according to the shapes of the plasma level curves into four types: type A, Cpmax(1) Cpmax(2); type D, Cpmax(1)=Cpmax(2). Assuming that the experimental results were obtained from fasted subjects, with the time of dose administration being a random variable, the frequency of the experimental curves having shape A, B, C, or D correlates extremely well with theoretical predictions. It is concluded that variable gastric emptying rates due to the motility cycle can account for plasma level double peaks. Furthermore, variable gastric emptying rates combined with the short plasma elimination half-life and poor gastric absorption of cimetidine can be the cause of the frequently observed plasma level double peaks.

Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects

Abstract: The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater gastric acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects,P<0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.

Carrier mediated transport of amino acids, their drug analogs*

Abstract: The oral absorption of amino acids, small peptides and their analogs has been studied in rats using single pass intestinal perfusion, The experimental data was analyzed using a modified boundary layer method permitting the calculation of intrinsic membrane absorption parameters. Cefatrizine, L-Dopa, cu-methyldopa, and L-PHE demonstrated concentration dependent absorption. Furthermore, the absorption of the amino acid analog, L-Dopa, was significantly inhibited by L-Leucine. Cefatrizine absorption was significantly inhibited by the peptide PHE-PHE (20 mM) whereas the amino acid L-PHE (100 mM) did not inhibit its absorption. The results clearly demonstrate that L-Dopa and a-methyldopa oral absorption occurs via the amino acidpathway, while cefatrizine absorption occurs via the peptide pathway. These results indicate that nutrient pathways may function as a possible route for the oral delivery of selected drugs.