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

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 Q_s/V_s, 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, C_pmax(1) pmax(2); type B, single peak; type C, C_pmax(1)>C_pmax(2); type D, C_pmax(1)=C_pmax(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.Notation A _s Amount of drug in the stomach - A _d Amount of drug in the duodenum - A _j Amount of drug in the jejunum - A _i Amount of drug in the ileum - A _p Amount of drug in the plasma - A _t Amount of drug in the peripheral compartment - Q _s Flow rate exiting the stomach - Q _d Flow rate exiting the duodenum - Q _j Flow rate exiting the jejunum - Q _i Flow rate exiting the ileum - V _s Volume of stomach contents - V _d Volume of duodenal contents - V _j Volume of jejunal contents - V _i Volume of ileal contents - V _p Volume of distribution - V _s ^o Initial volume of stomach contents - K _as Absorption rate constant of cimetidine from the stomach - K _ad Absorption rate constant of cimetidine from the duodenum - K _aj Absorption rate constant of cimetidine from the jejunum - K _ai Absorption rate constant of cimetidine from the ileum - K ₁₂ Distribution rate constant of cimetidine from plasma to tissue - K ₂₁ Distribution rate constant of cimetidine from tissue to plasma - K ₁₀ Elimination rate constant of cimetidine from the plasma - I Input of drug into the plasma from the gastrointestinal tract - DER Emptying rate of the drug from the stomach into the duodenum - C _pmax(1) First maximum drug concentration in the plasma - C _pmax(2) Second maximum drug concentration in the plasma - t _max(1) Time of first maximum drug concentration in the plasma - t _max(2) Time of second maximum drug concentration in the plasma This work was supported by the Smith Kline Beckman Corporation and the American Foundation for Pharmaceutical Education.