Variable gastric emptying and discontinuities in drug absorption profiles: dependence of rates and extent of cimetidine absorption on motility phase and pH.

The influence of various fasting-state gastrointestinal parameters on variability in absorption of cimetidine was studied using simulation and cimetidine administration as a duodenal infusion and as an oral tablet in fistulated mongrel dogs. In the simulation studies, the frequency of double-peak occurrence in plasma profiles was estimated employing average gastric emptying rates as well as interdigestive-migrating-motor-complex (IMMC) phase lengths that were systematically altered. Emptying rates and phase lengths were modeled as periodic step functions. Simulations indicated that double peaks occur when gastric emptying of the drug begins in early phase I or late phase II/III, which represent the periods of very low, medium, and high gastrointestinal motility, respectively. The incidence is increased for longer phase-I duration and higher elimination rate constants. For a compound with a 2 h elimination or disposition half-life, two concentration maxima (double peaks) were found in 12% of the simulated concentration-time profiles. The double peak frequency in simulated curves was considerably higher for t1/2 < 30 min. When cimetidine was administered to dogs as a duodenal infusion in the active and quiescent motility phases, discontinuous profiles were observed, although the variability of the various parameters was reduced when compared. Pharmacokinetic models were set up that were characterized by multi-segmental input (one- to 3-lag-time models were used) for the profiles resulting from oral and duodenal administration. The lag time for the first process characterized the onset of absorption. A significant difference between phases was detected for infusions at pH 8, where the initial lag time was longer in the quiescent phase. The mean input time (MIT) was calculated as the integral input parameter. There was a tendency for the MIT to be higher for pH 6 infusions than for pH 4 and pH 8. Bioavailability analysis indicated that cimetidine was more rapidly and completely absorbed at pH 8 than at pH 6. Bioavailability was also slightly higher at pH 4 than at pH 6. We concluded that gastric emptying increased the variability of the cimetidine concentration-against-time profiles and that it plays a role with respect to double-peak occurrence, although it is only one of several causative factors.