The influence of the interdigestive migrating myoelectric complex on the gastric emptying of liquids and oral absorption of cimetidine.

Abstract

A knowledge of the factors affecting gastric emptying is vital to our understanding of drug absorption because the rate of emptying often controls the rate of absorption after oral administration. In the case of cimetidine, it was hypothesized that emptying may result in variable absorption after a single dose and may account for the observed double peaks in the plasma level curve. A factor likely to influence gastric emptying in the fasted state is the cycle of fluctuating phasic contractions known as the interdigestive migrating myoelectric complex, IMMC. A physiological flow model demonstrated that variability in gastric emptying with IMMC phase could cause simulated plasma level double peaks. Important physiological factors included the (1) dosing time relative to the cycle, (2) length of phase after dosing, and (3) values of and variability in gastric emptying rates (GER). Important drug-related parameters were the absorption and elimination rate. Subsequent studies in healthy subjects were designed to determine the influence of the IMMC on the emptying rate of liquids and the oral absorption of cimetidine. After an initial lag period (LT), emptying of either 50 or 200 ml of water followed an exponential pattern. There was a significant dependence of gastric emptying on phase and volume of water administered with the dose. At 50 ml, the mean GER was successively greater during phase I, phase II, and late phase II/III (0.018, 0.083, 0.171 min$\sp{-1}$). The LT was greater during phase I than late phase II/III (19.1 vs. 3.8 min). At 200 ml, there was no difference in GER between phase I and II (0.11 min$\sp{-1}$), but GER during late phase II/III was greater (0.24 min$\sp{-1}$); LT was not dependent on phase (5 min). Interdigestive antral motility was not correlated with plasma level double peaks for cimetidine. In addition, reasonable values of and variation in GER resulted in minimal effect on simulated plasma level curves. Liquids emptied rapidly and variations in the GER after a single dose were minimal. Because of these factors, combined with the small absorption rate constant for cimetidine, it is unlikely that the phase dependent variability in gastric emptying is the major cause of double peaks.