| Co-Investigator(Kenkyū-buntansha) |
HIGAKI Kazutaka Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Associate Professor, 大学院医歯薬学総合研究科, 助教授 (60284080)
OGAWARA Ken-ich Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Assistant, 大学院医歯薬学総合研究科, 助手 (30291470)
KAWAI Kei-ichi Kanazawa University, Faculty of Medicine, Professor, 医学部, 教授 (30204663)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
In order to predict the oral absorption behaviors of drugs subjected to metabolism and/or secretion in the intestinal mucosa, we focused on P-glycoprotein (P-pg) as a secretion mechanism, and Cyp3A as a metabolism mechanism, and tried to develop the quantitative evaluation systems which allow us to estimate the effects of P-gp and Cyp3A on the oral absorption behavior. With oral dosing of dexamethasone (DEX) at 25-100 mg/kg/day for 2 days, rats having P-gp and Cyp3A at higher levels were prepared. High expression of P-gp and Cyp3A were recognized by estimating the secretion of rhodamine 123 in isolated intestinal sheets and the generation of 6β-0H of testosterone in microsome, respectively. Furthermore, we developed a vascularly perfused intestine-liver preparation, which makes it possible to evaluate the absorption, secretion, metabolism in the small intestine and the metabolism in the liver at the same time. The absorption kinetics of quinidine was successfully evaluated with a vascu
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larly perfused intestine-liver preparation.
On the other hand, many substrates for P-gp and/or Cyp3A are well known to be high lipophilic and poorly water-soluble. Therefore, we tried to predict the absorption behaviors of poorly water-soluble drugs after oral dosing as powders based on Gastrointestinal-Transit-Absorption model (GITA model). Griseofulvin, classified into Biopharmaceutics Classification System class II, was selected as a model compound. Dissolution process, assumed to obey the first-order kinetics, was incorporated into GITA model and the dissolution rate constants were determined by utilizing several existing media such as Japanese Pharmacopeia (JP) 1st solution, 2nd solution, fasted-state simulated intestinal fluids (FaSSIF) and fed-state simulated intestinal fluids (FeSSIF). However, simulated lines obtained with these dissolution rate constants were not in good agreement with the observed profile of plasma concentration of griseofulvin at all. Therefore, we developed a couple of new media, medium reflection in-vivo dissolution (MREVID) 1 and 2. Then, based on GITA model, the plasma concentration-time profile of griseofulvin after oral administration was predicted by utilizing the dissolution rate constants obtained with the new media. As a result, a simulation curve calculated by utilizing the dissolution rate constant obtained with MREVID 2 provided the best description of the observed line, which was good enough to predict Cmax and AUC although there was a little difference in Tmax between the observed and calculated values. Less
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