Prediction of the Plasma Concentration Profiles of Orally Administered Drugs in Rats on the Basis of Gastrointestinal Transit Kinetics and Absorbability

Sawamoto, Taiji; Haruta, Shunji; Kurosaki, Yuji; Higaki, Kazutaka; Kimura, Takeshi

doi:10.1111/j.2042-7158.1997.tb06823.x

Cited by 78 publications

(85 citation statements)

References 20 publications

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“…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.…”

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“…Here, we would like to introduce the concept and the methodology of GITA Model, and to show its usefulness by reviewing the results obtained for the absorption kinetics of drugs with various characteristics. 12) To develop the GITA model, GI-tract was, first of all, divided into eight segments (stomach, duodenum, upper jejunum, lower jejunum, upper ileum, lower ileum, cecum and large intestine) and the transit of an unabsorbable drug from a segment to the next segment was approximated to follow a first-order kinetics as shown in Fig. 1 (GI Transit Kinetic (GITK) Model 12) ).…”

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confidence: 99%

“…12) To develop the GITA model, GI-tract was, first of all, divided into eight segments (stomach, duodenum, upper jejunum, lower jejunum, upper ileum, lower ileum, cecum and large intestine) and the transit of an unabsorbable drug from a segment to the next segment was approximated to follow a first-order kinetics as shown in Fig. 1 (GI Transit Kinetic (GITK) Model 12) ). The absorbable drug transits from a segment (i) to the next segment (iϩ1) with the segmental absorption (a first-order absorption) as shown in Fig.…”

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Gastrointestinal Transit and Drug Absorption

Kimura

Higaki

2002

Biological & Pharmaceutical Bulletin

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170

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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...

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Gastrointestinal Transit and Drug Absorption

Kimura

Higaki

2002

Biological & Pharmaceutical Bulletin

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170

114

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“…Various pharmacokinetic parameters were applied to mathematically simulate the processes of drug transit, degradation, absorption, distribution, and elimination. The transit and elimination rate constants were assumed to be the same as those of phenol red, a non-absorbable marker, in male Wistar rats (32). The degradation and absorption rate constants were experimentally determined.…”

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confidence: 99%

“…The rate constants of GI-transit, absorption, and deposition were used as modeling parameters. The transit rate constants of the lower ileum, k tr,1 (0.46 h −1 ), and cecum, k tr,ce (0.00001 h −1 ), were obtained from literature for male Wistar rats (32). The average rate constants of degradation, k deg (30 h −1 ) and absorption, k a (0.13 h −1 ), were determined by experiments described above.…”

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Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats

et al. 2007

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Purpose-To quantitate and predict colon-specific 9-aminocamptothecin (9-AC) release from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-9-AC conjugate and its absorption behavior after oral administration in rats.Methods-Drug distribution in the gastrointestinal (GI) tract and the plasma concentration-time profile of 9-AC released from the HPMA copolymer conjugate were predicted using the degradation, transit, and absorption rate constants in cecum. The fate of 9-AC in cecum and liver was measured by in-situ cecum absorption and liver perfusion.Results-Following oral administration of the conjugate, 9-AC was released rapidly in cecum. Based on the pharmacokinetic model, up to 60% of the dose was in the cecum at ∼6 h, and 7% of the dose still remained there at 24 h. The predicted plasma concentration curve for released 9-AC after an oral dose of 3 mg/kg of 9-AC equivalent increased gradually and reached a peak of 98 nM at 7 h, then started decreasing slowly to 16 nM at 24 h. The bioavailability value was estimated as 0.31 after the first-pass elimination.Conclusions-A pharmacokinetic model delineated the impact of GI transit, drug absorption rate, and first-pass metabolism on drug disposition following oral administration of HPMA copolymer-9-AC conjugate in rats.

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Evaluation of absorption kinetics of orally administered theophylline in rats based on gastrointestinal transit monitoring by gamma scintigraphy

Haruta

Kawai

Jinnouchi

et al. 2001

Journal of Pharmaceutical Sciences

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The gastrointestinal (GI) transit and absorption of orally administered theophylline, a highly absorbable drug without presystemic elimination, were investigated under fasted and fed conditions using three rats in a crossover study. To evaluate the GI transit rate for each segment in vivo, a noninvasive technique, gamma scintigraphy, was employed using a nonabsorbable compound, Tc-labeled diethylenetriamine pentaacetic acid (DTPA). Using a gamma scintigraphic technique it is possible to simultaneously evaluate the GI transit and absorption of orally administered drug in the same individual. Theophylline was simultaneously administered along with [ 99m Tc]DTPA to animals in the fasted and fed states. Each GI transit pattern, simulated using the GI transit±kinetic model with a lag time factor, was well ®tted to the experimental data. Gastric emptying rate varied in each study, even under the same experimental condition. The GI transit pattern for each segment was highly variable, especially in animals in the fed state. This inconsistency in transit pattern was mainly due to the variability in gastric emptying, which was much slower in animals in the fed compared with the fasted state. However, in spite of a large variability of GI transit kinetics, the plasma concentration±time curves of theophylline were well predicted by the GI transit±absorption model using the individual GI transit parameters obtained in the study. The absorption rate of theophylline was considerably reduced in animals in the fed state, because of the reduction of gastric emptying rate. Analysis using GI transit±absorption model and gamma scintigraphic technique made it possible to estimate the variable absorption kinetics regulated by GI transit with huge variability. ß

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Prediction of the Plasma Concentration Profiles of Orally Administered Drugs in Rats on the Basis of Gastrointestinal Transit Kinetics and Absorbability

Cited by 78 publications

References 20 publications

Gastrointestinal Transit and Drug Absorption

Gastrointestinal Transit and Drug Absorption

Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats

Evaluation of absorption kinetics of orally administered theophylline in rats based on gastrointestinal transit monitoring by gamma scintigraphy

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