Use of a Pharmacokinetic Model Incorporating Discontinuous Gastrointestinal Absorption to Examine the Occurrence of Double Peaks in Oral Concentration–Time Profiles

Abstract

Double peaks in the plasma concentration–time profile following oral administration have been reported for several compounds. A pharmacokinetic model incorporating discontinuous absorption was developed to simulate concentration-time profiles with double peaks. The gastrointestinal (GI) tract was divided into N compartments, with absorption occurring only from the second and Nth compartments. A two-compartment model was used to describe systemic drug disposition. The effect of gastric emptying and GI transit rate constants (K_l and K_t, respectively), number of hypothetical gut compartments, and absorption rate constant at each site (K_a1, K_a2) on the time of occurrence of each peak (T_pl, T_p2), the theoretical fraction of the dose absorbed at each site (Φ ₁, Φ ₂), and the contribution of the second site to systemic drug exposure (expressed as Φ _2rel) were examined. Simulated concentration–time profiles demonstrated that T_p2 was determined by K_t and N, while T_p1 was determined by K_l and K_t. Changes in K_a1 and K_a2 had no effect on T_p1 or T_p2. Φ₁ , Φ₂, and Φ _2rel were determined by K_al, K_a2, and K_t, and simulations indicated that a secondary peak in the concentration-time profile will be evident only when Φ_2rel is substantial. In addition, concentration–time data for ranitidine and cimetidine, which displayed double peaks, were fit with the model. The present model described both data sets well, and realistic pharmacokinetic and physiologic parameters (absorption rate constants, systemic bio-availabilities, GI residence times) were obtained.