| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Hiroshi The University of Tokyo, The University of Tokyo Hospital, professor (80206523)
ITO Kosei The University of Tokyo, The University of Tokyo Hospital, associate professor (30323405)
TAKADA Tappei The University of Tokyo, The University of Tokyo Hospital, assistant professor (90376468)
SUGAWARA Yasuhiko The University of Tokyo, The University of Tokyo Hospital, associate professor (90313155)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Some oral drugs are metabolized during the process of absorption at the intestinal wall, and this would hamper efficacy of the drug seriously. On the other hand, it has been reported that intestinal expression of a representative drug metabolizing enzyme, CYP3A4, is very low compared with that in the liver. Thus, the prediction of oral availability is often troublesome since observed intestinal metabolism is theoretically unexplainable from in vitro data with pharmacokinetic models currently used. Moreover, information on in vivo intestinal metabolism is still limited as a number of drugs is very small for those intestinal metabolism is evaluated separating unambiguously from the hepatic metabolism.
Considering these issues, this study was aimed to improve methods for pharmacokinetic analysis of intestinal metabolism, focusing on the following three topics : First, we developed a new method for estimation of the intestinal metabolism from in vivo pharmacokinetic data to extend knowledge
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of intestinal metabolism for many drugs as possible. Second, we considered the physiological structure, intrinsic metabolic clearance, and membrane permeability involved in the process of intestinal absorption, and proposed a local intestinal pharmacokinetic model. In this model, a role of permeability of the basolateral membrane of the intestinal wall, rather than the apical membrane which faces to the intestinal lumen, will be emphasized. In addition, the proposed local model was compared with Q-gut model, an empirical pharmacokinetic model currently used for estimation of the intestinal availability. And third, the above local pharmacokinetic model that describes radial transfer of drug in the intestine was extended to a full intestinal model considering movements of a drug upper from the stomach through the duodenum, jejunum, ileum and then lower to the column. The full model is described mathematically by partial differential equations, and explained gradual movements of drug in the gastro-intestine with dispersion and vectorial transport. The full model is applicable to nonlinear pharmacokinetics such as saturations of metabolism and transport by using a numeric calculation method.
The current study provided a theoretical framework to consider various effects such as permeability, metabolism, and transportation on the intestinal metabolism and to the availability, and will be helpful for more precise prediction of pharmacokinetics from in vitro data. Less
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