Quantiative prediction of intestinal availability of CYP3A4 substrates
| Project/Area Number |
17590135
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kitasato University |
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Principal Investigator |
ITOH Tomoo Kitasato University, School of Pharmacy, Professor (30223168)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | first-pass effect / small intestine / CYP3A4 / human intestinal microsomes / Caco-2 cells |
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| Research Abstract |
Intestinal availability (Fg) of CYP3A4 substrates were quantitatively predicted based on the in vitro metabolic study with human intestinal microsomes and the efflux study with Caco-2 cells. Alprazolm (ALP), triazolam (TRZ), midazolam (MDZ), carbamazepine (CBZ) and testosterone (TST) were used as model CYP3A4 substrates. Fg values were predicted according to the single compartment kinetic model, and the more precise model was also developed which incorporated the transit of the drug in the intestinal lumen, absorption into the intestinal epithelial cells, the metabolism in the epithelial cells and the exit to the portal vein: Intestinal Transit, Absorption and Metabolism (ITAM) model.
Fg values of ALP, TRZ and CBZ were well predicted according to the single compartment kinetic model. However, the predicted Fg of MDZ was smaller than the reported Fg in humans. Since it has been reported that MDZ shows mechanism-based inhibitor like characteristics in CYP3A4 expression system, we studied if MDZ exhibits mechanism-based inhibitor like characteristics in human intestinal microsomes. MDZ did exhibit mechanism-based inhibitor like characteristics in human intestinal microsomes, and the Fg of MDZ was predicted using an ITAM model with mechanism based inhibitor like characteristics. The predicted Fg value of MDZ became close to the reported value, which indicated that MDZ acts as a mechanism-based inhibitor in the epithelial cells and that the metabolism of MDZ itself is inhibited in the process of absorption.
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Report
(3 results)
Research Products
(19 results)
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[Book] パートナー薬剤学2007
Author(s)
伊藤 智夫
Total Pages
30
Publisher
南江堂
Description
「研究成果報告書概要(和文)」より
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