Prediction of plasma concentration–time curve of orally administered theophylline based on a scintigraphic monitoring of gastrointestinal transit in human volunteers

Haruta, Shunji; Kawai, Keiichi; Nishii, Ryuichi; Jinnouchi, Seishi; Ogawara, Ken Ichi; Higaki, Kazutaka; Tamura, Shozo; Arimori, Kazuhiko; Kimura, Takeshi

doi:10.1016/s0378-5173(01)00942-5

Cited by 18 publications

(10 citation statements)

References 19 publications

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“…In the case of humans, PEPT1 are expressed mainly in upper segments such as duodenum and jejunum (59,61) and the expression level is much lower than that in rats (60). Considering the very short residence time in such upper segments as well (30,35,62), the contribution of PEPT1 to cephalexin absorption might not be so large in humans. It was also suggested that passive diffusion might contribute to cephalexin absorption in humans (9).…”

Section: Resultsmentioning

confidence: 99%

Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

et al. 2008

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Section: Resultsmentioning

confidence: 99%

Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

et al. 2008

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“…The model described below is used as a first best estimate. In the literature the RTD in the gastrointestinal tract has been described in different ways (11,17,29). Most of these are based on exponential decay equations the summarized distributed intervals of which result in S-shaped, cumulative curves.…”

Section: Methodsmentioning

confidence: 99%

“…There are relatively few reports in the literature of attempts to model the gastrointestinal tract. Most of the articles are focused on the residence time distribution (RTD) in the stomach and the gut (11,18,26,29). Wilkinson (29,30) performed an extensive modeling study of the gastrointestinal tract.…”

mentioning

confidence: 99%

In Silico Model as a Tool for Interpretation of Intestinal Infection Studies

de Jong,

Vissers,

van der Meer

et al. 2007

Appl Environ Microbiol

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In nutrition research the number of human in vivo experiments is limited because of the many restrictions and the high costs of testing in humans. Up to now predictive computer models aiming to enhance research have been rare or too complex, with many nonmeasurable adjustable parameters. This study aimed to develop a basic physicochemical computer model for a first quantitative interpretation of results obtained from in vivo intestinal experiments with bacteria. This new modeling approach is validated with results obtained from gut infection studies in vivo. The design of the model is described, and its ability to reproduce experimental data is evaluated. The model predictions are compared with new experimental data. The phenomena that take place in the gastrointestinal tract are summarized by model constants for growth, adherence, and release of bacteria. Although the model is far from describing all details and many processes in the intestine are combined, the model calculation results lead to reasonable conclusions and interesting hypotheses. One of these hypotheses concluded from the model outcomes is that Escherichia coli bacteria have a much lower intestinal growth rate in humans than in rats. Extra laboratory validation experiments proved the reliability of this hypothesis predicted by the model. In addition, the known protective effect of dietary calcium and detrimental effect of clindamycin on the growth and adherence of Salmonella bacteria could be quantified. From these results it is clear that the model enhances the interpretation of in vivo gastrointestinal experiments and will facilitate research trajectories towards new functional foods that improve resistance to pathogenic bacteria in humans.In science more and more mathematical models are being described for use in experimental design, interpretation of experimental results, prediction of new experimental results, or scaling up from small-scale experiments to industrial-scale production plants. The first application of these mathematical models in general could be found in the chemical industry in the 1960s. The food industry started to use models in the early 1990s. Nowadays predictive computer (in silico) models play a major role in the design of food products, aiming at reducing the number of expensive experiments on the pilot or industrial scale (10).In human nutrition research the use of mathematical models is very limited. The first reason is the extreme complexity of the system to be modeled: the human being. Especially in the case of infection studies, most of the research is performed with model studies with animals or with in vitro experiments. The number of human in vivo experiments is limited because of the many restrictions and the high costs of testing in humans. There are relatively few reports in the literature of attempts to model the gastrointestinal tract. Most of the articles are focused on the residence time distribution (RTD) in the stomach and the gut (11,18,26,29). Wilkinson (29,30) performed an extensive modeling study o...

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“…2,[10][11][12][13][14] T h ev a l u e so fk ai for theophylline were cited from our previous paper. 2,[10][11][12][13][14] T h ev a l u e so fk ai for theophylline were cited from our previous paper.…”

Section: Methodsmentioning

confidence: 99%

“…[3][4][5][6] That is to say, the drug absorption from GI tract is determined by two major factors, the permeability of GI mucosa and the transit rate in GI tract, 7) although the intestinal metabolism and secretion must be given as a factor in‰uencing the drug absorption for some drugs. 13) Furthermore, we have successfully predicted the plasma concentration-time proles of both a prodrug and its parent drug after oral administration of a prodrug. We have already developed the GI-Transit-Absorption (GITA) model and reported that the absorption behaviors of drugs with various absorption-characteristics can be analyzed and predicted by GITA model after they were orally administered as an aqueous solution.…”

Section: Introductionmentioning

confidence: 97%

Analysis and Prediction of Absorption Behavior for Theophylline Orally Administered as Powders Based on Gastrointestinal-transit-Absorption (Gita) Model

Kadono

Yokoe

Ogawara

et al. 2002

Drug Metabolism and Pharmacokinetics

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Absorption behavior of theophylline, categorized into Class I of Biopharmaceutics Classification System, orally administered as powders in rats was analyzed and predicted by Gastrointestinal-Transit-Absorption (GITA) model, which was modified to describe GI-transit kinetics and dissolution of powders orally administered. First of all, GI-transit kinetics of glass beads was examined to describe the transit kinetics of powders through GI tract in rats. The results showed that the gastric emptying of glass beads was slower than that of solution, but that there was not much difference in the transit rate constants through the small intestine and cecum between glass beads and solution. Furthermore, to introduce the dissolution process of theophylline powders into GITA model, an in-vitro dissolution test was examined for theophylline powders according to the Japanese Pharmacopoeia paddle method. The dissolution rate constants calculated based on the mean dissolution time were not so different in the range of pH from 1.2 to 6.5. Using the parameters for GI transit, dissolution and absorption obtained, the plasma concentration-time profile of theophylline after oral administration as powders to rats was predicted based on GITA model. The profile calculated was significantly correlated with the observed time course of plasma concentration for theophylline, and the parameters such as C(max) and AUC based on the predicted curve coincided with those on the observed data, showing that GITA model is useful for the prediction of the absorption behavior of drugs administered as powders. The simulation studies showed that about 80% of orally administered theophylline powders dissolved in the stomach and that the remaining powders rapidly moved to the lower jejunum and ileum, where they dissolved. Furthermore, it was suggested that theophylline is absorbed mostly in the upper small intestine, duodenum, upper jejunum and lower jejunum, after its oral administration as powders.

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Prediction of plasma concentration–time curve of orally administered theophylline based on a scintigraphic monitoring of gastrointestinal transit in human volunteers

Cited by 18 publications

References 19 publications

Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats

In Silico Model as a Tool for Interpretation of Intestinal Infection Studies

Analysis and Prediction of Absorption Behavior for Theophylline Orally Administered as Powders Based on Gastrointestinal-transit-Absorption (Gita) Model

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