| Project/Area Number |
11470509
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B).
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
応用薬理学・医療系薬学
|
|---|
| Research Institution | Graduate School of Pharmaceutical Sciences, The University of Tokyo |
|---|
Principal Investigator |
SUGIYAMA Yuichi The Univ.of Tokyo, Graduate School of Pharm.Sci., Professor, 大学院・薬学系研究科, 教授 (80090471)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KUSUHARA Hiroyuki The Univ.of Tokyo, Graduate School of Pharm.Sci., Research Associate, 大学院・薬学系研究科, 助手 (00302612)
KATO Yukio The Univ.of Tokyo, Graduate School of Pharm.Sci., Research Associate, 大学院・薬学系研究科, 助手 (30251440)
SUZUKI Hiroshi The Univ.of Tokyo, Graduate School of Pharm.Sci., Assistant Professor, 大学院・薬学系研究科, 助教授 (80206523)
ITO Kiyomi Kitasato University, Faculty of Pharm.Sci., Assistant Professor, 薬学部, 講師 (60232435)
|
|---|
| Project Period (FY) |
1999 – 2000
|
| Project Status |
Completed (Fiscal Year 2000)
|
| Budget Amount *help |
¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2000: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 1999: ¥8,900,000 (Direct Cost: ¥8,900,000)
|
|---|
| Keywords | Transporter / Organic anion / Biliary excretion / Urinary excretion / MRP2 / MRP3 / oatp1 / oat3 |
|---|
| Research Abstract |
Therapeutic agents administered to the body are generally eliminated by the metabolism and/or excretion both in the liver and kidney. The elimination route (liver or kidney) of the drugs has been believed to mainly depend on the physicochemical properties of the drugs. However, the recent advance in the molecular biology revealed that many types of drug transporters are expressed in both organs and involved in drug disposition. Therefore, the present study focused on the function of such transporters in vivo to determine the drug elimination route. We have established the gene transfectant systems both for Ntcp and Oatp1 and analyzed their substrate specificity. Many types of therapeutic agents were identified as substrates of Oatp1 whereas Ntcp has the narrow substrate specificity within the bile acids. By comparing the transport activity between the hepatocytes and such transfectants, we have estimated the contribution ratio of Oatp1 to the overall uptake of each substrate by hepatocytes. In this study we also identified new clones, Oat3 and Oat4, which are expressed in the liver. Substrate specificity of Mrp3 which is expressed on the basolateral membrane of the liver was examined. We found that Mrp3 accepts bile acids as substrates and is involved in their efflux from the hepatocytes in the isolated rat liver perfusion system. Cholestatic condition as well as phenobarbital treatment results in the overexpression of Mrp3 which come from at least partially the increase in mRNA level. Since Mrp3 accept many types of organic anions as substrates, these findings imply that the specific transport systems should be considered to be involved in the efflux of drugs from the liver to blood.
|
