Gastrointestinal Transit and Drug Absorption

Abstract

Oral drug administration is the most convenient and common for drug therapy and it is, therefore, very important and useful to estimate the absorbability of drugs and to predict the plasma concentration profile of drugs after oral administration for the development of novel drugs and/or novel dosage form and the designation of the dosage regimen. Generally, the absorbability of drugs has been estimated by in-situ recirculation studies, in-situ closed loop studies or the analysis by the simple compartment model. The information which can be obtained from these approaches is usually an absorption rate constant, ka. The ka value is generally the averaged one throughout the intestinal tract. However, there is the site-difference in drug absorbability [1][2][3][4] and variable residence time of drugs in each segment must make the contribution of each segment to drug absorption changed, resulting in the different absorbability as a whole. As for the drug absorption after oral administration, the gastrointestinal (GI) transit of a drug is also an important factor to determine the drug absorption and is so variable, as was influenced by not only individual differences, 5) but also the dosage conditions like meals, 6) disease states 7) and so on. Therefore, the absorbability and the residence time in each segment are the major determining factors for drug absorption after oral administration and very important for the analysis of drug absorption kinetics and the estimation of, and the prediction of plasma concentration profiles of drugs. However, the analysis and the estimation of drug absorption after oral administration have been usually performed by a simple compartment model, where even a process of gastric emptying is not included often. This kind of simple model cannot describe the irregular shape in the plasma concentration, which is often observed. Therefore, several models were proposed to analyze the plasma profile, [8][9][10][11] but they are not necessarily based on the practical phenomena, i.e. GI transit and site-different drug absorbability.We have developed a GI-Transit-Absorption (GITA) Model containing the GI transit and absorption processes to analyze and predict the plasma concentration profile after oral administration of aqueous drug solution.12) Although several efficient methods to estimate the absorption of orally administered drug by analyzing the GI disposition following oral administration (GI disposition analysis) have been reported, some are only focused on the gastric emptying based on a model having a stomach and an intestine compartment. 13,14) The other one estimated the intestinal transit of a drug using polyethylene glycol 4000 as a nonabsorbable marker, 10) but the actual data of intestinal transit were not utilized enough to analyze and predict the drug absorption kinetics. Although the analytical procedures for plasma profile of a drug absorbed from successive absorption sites along the GI tract have been also reported, [16][17][18] they just showed the concept and/or simulation stu...

SIMDOT-AbMe: Microphysiologically Based Simulation Tool for Quantitative Prediction of Systemic and Local Bioavailability of Targeted Oral Delivery Formulations

“…In the present work, a physiologically relevant simulation tool was developed to model the absorption, biotransformation, metabolism, and clearance of 5-ASA. In the model presented, passive absorption, saturable absorption, biotransformation, and transit kinetics were simultaneously considered, whereas general purpose absorption and transit models (Ito et al, 1999;Agoram et al, 2001;Kimura and Higaki, 2002) exclude extracellular metabolism and exsorption (efflux transport). On the other hand, not unlike our model, the traditional and segregated-flow models developed by Cong et al (2000) comprehensively illustrate the interactions among the effective flow to the intestine, absorption rate, and intestinal epithelial cell activities including enzymatic, secretory, and metabolism activities.…”

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

“…Chiou et al quantitatively studied the impact of the unstirred water layer adjacent to the intestinal membrane on the rate and extent of absorption of passively absorbed drugs with different membrane absorption half-lives (10 -300 min) in humans (Chiou 1994). Results of this analysis suggested that the presence of the unstirred water layer is generally expected to have a relatively mild or insignificant effect on the rate of absorption and an insignificant effect on the extent of absorption (Kimura and Higaki 2002).…”

“…The absorption rate of a drug molecule is generally a function of drug absorption through the GIT, which is determined by the residence time and absorption in each GIT segment (Kimura and Higaki 2002). In general, gastric transit time impacts the systemic exposure of rapidly dissolved and well absorbed drugs.…”

“…In contrast to gastric transit time, intestinal transit time is independent of the feeding conditions and the physical composition of the intestinal contents (Garanero et al 2005) . The human intestinal transit time is ~3 -4 h (DeSesso and Jacobson 2001; Kimura and Higaki 2002). Several studies suggested that in human small intestine, there is a gradient of velocity where the small intestinal transit in the proximal intestine was faster compared with the distal intestine.…”

The virtual laboratory approach to pharmacokinetics: design principles and concepts

“…The quality and predictive power of new models will be judged in comparison with experimental data as well as in comparison with other models (as an example see, e.g., the study in [14]). A variety of different models for oral absorption are avaliable [15][16][17][18][19]. By comparing these absorption models for different test compounds, it would be possible to understand the "domain of applicability" of each model, i.e., under which conditions and for which class of compounds the models give the most reliable predictions.…”