| Project/Area Number |
03557111
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
INUI Kenichi Tokyo Medical and Dental University, School of Medicine, Department of Hospital Pharmacy, Professor, 医学部, 教授 (70034030)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Hideyuki Tokyo Medical and Dental University, School of Medicine, Department of Hospital, 医学部, 助手 (40225727)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 1992: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1991: ¥4,400,000 (Direct Cost: ¥4,400,000)
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| Keywords | Intestinal Absorption / Tubular Secretion / Cultured Epithelial Cell / Transcellular Transport / Cephalosporin Antibiotic / Dipeptide / Proton-Coupled Transport / プロトン共役輸送 / アミノ-β-ラクタム抗生物質 |
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| Research Abstract |
In the development of new remedies, the use of animals in evaluating drug safety is costly, time-consuming and increasingly criticized by animal-welfare groups. Alternative methods have been expected to reduce the number of animals needed. In this study, we attempted to establish in vitro method for the evaluation of the drug absorption and secretion using cultured intestinal and renal epithelial cells.
1) Characterization of intestinal and renal epithelial cell cultures: The human colon adenocarcinoma cell line Caco-2 and the pig kidney epithelial cell line LLC-PK_1 grown on microporous membrane filters (Transwell^<TM>) were used as models for the analysis of epithelial functions in the intestine and in the proximal tubules.
2) Drug transport in the Caco-2 cell monolayers: The accumulation and the transepithelial transport of p.o. cephalosporins and bestatin by Caco-2 cell monolayers were unidirectional, corresponding to the absorptive process in the intestinal mucosa. The accumulation and the transepithelial transport were inhibited by dipeptides, and were stimulated by acidifying the apical incubation medium, suggesting the H^+/dipeptide cotrasport system.
3) Drug transport in the LLC-PK_1 cell monolayers: Tetraethylammonium, cimetidine, procainamide and quinidine (organic cations) were accumulated progressively in the LLC-PK_1 cell monolayers from the basolateral side and were transported unidirectionally to the apical side, corresponding to the secretion in the proximal tubules. The transcellular transport of these drugs was saturable and was stimulated by lowering pH of the apical side, indicating the H^+/organic cation antiport system.
In conclusion, the Caco-2 and the LLC-PK_1 cell monolayers grown on microporous membrane filters can be useful model systems to evaluate the drug absorption and secretion and to study the drug interaction.
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