Gastrointestinal Transit Absorption model

Furthermore, the Pefr data can be integrated with solubility/dissolution data to predict the oral absorption from the solid dosage form (see Chapter 10). Gastrointestinal transit absorption model (GITA) [12, 13], advanced compartmental absorption and transit model (ACAT, GastroPlus), advanced drug absorption and metabolism model (ADAM, SimCYP) and so on have been reported as useful integration models (see Chapter 10). 

Other than the different approaches mentioned above, commercial packages such as GastroPlus (Simulations Plus, Lancaster, CA) [19] and IDEA (LionBioscience, Inc. Cambridge, MA) [19] are available to predict oral absorption and other pharmacokinetic properties. They are both based on the advanced compartmental absorption and transit (CAT) model [20], which incorporates the effects of drug moving through the gastrointestinal tract and its absorption into each compartment at the same time (see also Chapter 22). 

The basis for all CAT models is the fundamental understanding of the transit flow of drugs in the gastrointestinal tract. Yu et al. [61] compiled published human intestinal transit flow data from more than 400 subjects, and their work showed the human mean small intestinal transit time to be 199 min. and that seven compartments were optimal in describing the small intestinal transit process using a compartmental approach. In a later work, Yu et al. [58] showed that between 1 and 14 compartments were needed to optimally describe the individual small intestine transit times in six subjects but in agreement with the earlier study, the mean number of compartments was found to be seven. This compartmental transit model was further developed into a compartmental absorption and transit (CAT) model ([60], [63]). The assumptions made for this CAT model was that no absorption occurs in the stomach or in the colon and that dissolution is instantaneous. Yu et al. [59] extended the CAT model... 

Another important advance adding to the value of PBPK modeling in the pharmaceutical industry are physiological, mechanistic models developed to describe oral absorption in humans and preclinical species. Oral absorption is a complex process determined by the interplay of physiological and biochemical processes, physicochemical properties of the compound and formulation factors. Physiologically based models to predict oral absorption in animals and humans have recently been reviewed [18, 19] and several models are now commercially available. The commercial models have not been published in detail because of proprietary reasons but in essence they are transit models segmenting the gastrointestinal tract... 

These models assume that oral drug absorption takes place under equilibrium conditions. Spatial or temporal aspects of the drug dissolution, transit and uptake and the relevant physiological processes in the gastrointestinal tract are not taken into account. Only drug-related properties are considered as the key parameters controlling the absorption process. 

These simple models based on the assumption of a single intestinal compartment have been refined to the advanced compartmental absorption and transport model that allows transit and differential expression of enzymes and transporters down the length of the gastrointestinal tract including pH, fluid, and blood flow differences [3]. The ACAT model is based on a series of integrated differential equations and has been implemented in the commercial software Gastroplus (see Chapter 17). 

There appears to be large differences in the manner and rate of absorption of the pyrethroids from the gastrointestinal tract, implying that GI advanced compartmen-tal transit models (ACAT) need to be included in PBPK models. This is especially true of the absorption of an oral dose of tefluthrin in male rats, in which 3.0-6.9%, 41.3-46.3%, and 5.2-15.5% of the dose is eliminated in urine, feces, and bile, respectively (0-48 h after administration). Several percutaneous studies with the pyrethroids strongly support the belief that these insecticides are not readily absorbed, but remain on the surface of the skin until they are washed off. In one particular study (Sidon et al. 1988) the high levels of permethrin absorption through the forehead skin (24—28%) of the monkey was reported over a 7- to 14-days period. Wester et al. (1994) reported an absorption of 1.9% of pyrethrin that had been applied to the forearm of human volunteers over a 7-days period. 

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