title: 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 (Kl and K1, respectively), number of hypothetical gut compartments, and absorption rate constant at each site (Ka1, Ka2) on the time of occurrence of each peak (Tp1, Tp2), the theoretical fraction of the dose absorbed at each site (phi 1, phi 2), and the contribution of the second site to systemic drug exposure (expressed as phi 2rel) were examined. Simulated concentration-time profiles demonstrated that Tp2 was determined by Kt and N, while Tp1 was determined by K1 and Kt. Changes in Ka1 and Ka2 had no effect on Tp1 or Tp2. phi 1, phi 2, and phi 2rel were determined by Ka1, Ka2, and Kt, and simulations indicated that a secondary peak in the concentration-time profile will be evident only when phi 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 bioavailabilities, GI residence times) were obtained.
authors.affiliation: Division of Pharmaceutics, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
authors.forename: A B
authors.initials: AB
authors.lastname: Suttle
authors.forename: G M
authors.initials: GM
authors.lastname: Pollack
authors.forename: K L
authors.initials: KL
authors.lastname: Brouwer
mesh_terms: D000284:Administration, Oral; D002927:Cimetidine / Q000097:blood / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D008954:Models, Biological; D011899:Ranitidine / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D002927:Cimetidine; D011899:Ranitidine