Dose Dependency in the Gastrointestinal Absorption of Cefatrizine : Correlation between in Vivo and in Situ
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概要
- 論文の詳細を見る
We evaluated the dose-dependent (saturable) gastrointestinal absorption of cefatrizine, an aminocephalosporin transported by peptide carriers, in rats by a physiological mechanism-based approach to clarify its absorption characteristics and to examine the in vitro (in situ)-in vivo correlation in intestinal transport. With an increase in oral dose (μmol/5 ml/kg) from 5 (low) to 50 (high), the intestinal absorption rate constant (k_a), which was estimated by analysis of gastrointestinal disposition, decreased markedly, from 0.301 to 0.056min^<-1>. This decrease was ascribable to the saturability of intestinal membrane transport, of which the concentration dependency in the perfused intestine was similar in extent to the dose dependency in k_a. However, the apparent absorption rate constant (k_a'), which was estimated by analysis of plasma concentrations after oral administration, decreased only modestly from 0.037 to 0.023 min^<-1>. This was associated with the result that, at the low dose, k_a' was far smaller than k_a and comparable with k_g (gastric emptying rate constant), suggesting gastric emptying-limited absorption. At the high dose, where intestinal cefatrizine absorption was less efficient, k_a' was closer to k_a than k_g. It was also observed that the bioavailability was close to unity, independent of dose, suggesting that the intestinal transit time is long enough to achieve complete absorption, even at the high dose, where intestinal cefatrizine absorption is less efficient. Thus, it was found that the effect of saturability in the intestinal transport of cefatrizine is apparently attenuated in its overall gastrointestinal absorption because of the involvement of gastric emptying and intestinal transit time as additional physiological factors to define absorption. It was also found that a scaling factor is required to correlate the intestinal membrane transport between in vitro (in situ) and in vivo, though this remains to be verified to be utilized for developing oral drug delivery strategies and optimizing oral drug therapy.
- 公益社団法人日本薬学会の論文
- 1998-06-15
著者
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林 弥生
College Of Pharmacy Kinjo Gakuin University
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Watanabe J
School Of Pharmacy Aichi Gakuin University
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YUASA Hiroaki
Faculty of Pharmaceutical Sciences, Nagoya City University
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WATANABE Jun
Faculty of Pharmaceutical Sciences, Nagoya City University
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MATSUDA Kenji
Faculty of Pharmaceutical Sciences, Nagoya City University
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Matsuda K
Faculty Of Pharmaceutical Sciences Nagoya City University
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Matsuda K
Tohoku Univ. Sendai Jpn
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Yuasa Hiroaki
Department Of Biopharmaceutics Graduate School Of Pharmaceutical Sciences Nagoya City University
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Yuasa Hiroaki
Faculty Of Pharmaceutical Sciences Nagoya City University
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Watanabe J
Department Of Pharmaceutics College Of Pharmacy Nihon University
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Hayashi Y
Life Science Laboratories Central Research Laboratories Ajinomoto Co. Inc.:pharmaceuticals Research
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Hayashi Yayoi
Department Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Nagoya City University
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Matsuda Kenji
Faculty Of Engineering Kyushu Institute Of Technology
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Watanabe Jun
Faculty Of Education Tokyo Gakugei University:(present Address)creative Research Initiative "so
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