Molecular basis for quantitative prediction of drug-drug interaction at excretion process
| Project/Area Number |
16590108
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Medical pharmacy
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
KATO Yukio Kanazawa University, Graduate School of Natural Science and Technology, Associate Professor, 自然科学研究科, 助教授 (30251440)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TSUJI Akira Kanazawa University, Graduate School of Natural Science and Technology, Professor, 自然科学研究科, 教授 (10019664)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
|
|---|
| Keywords | Drug-drug interaction / Transporter / Drug disposition / Membrane transport / Pharmacokinetics / Renal tubular secretion / Kidney / Renal excretion |
|---|
| Research Abstract |
Recent progress in molecular biology has revealed predominant roles of many types of xenobiotic transporters in drug secretion into the urine and bile, leading to possible occurrence of drug-drug interaction at the excretion processes. Therefore, it is expected to predict the interaction based on in vitro experimental system. This study aimed to clarify molecular basis for the prediction of drug-drug interaction at the excretion process in liver and kidney. As model drugs that are excreted into the bile and urine, a novel uric acid generation inhibitor Y-700 and a novel diuretic M17055 were used. We have suggested involvement of Na^+-dependent organic anion transport system, other than OATP family, in hepatic uptake of Y-700, part of Y-700 uptake being mediated by bile acid transporter NTCP. We have also clarified important role of OAT1 in renal uptake of M17055. Furthermore, we have identified direct interaction of certain types of transporters, that are expressed on apical membranes in kidney and/or small intestine, with PDZ domain containing proteins PDZK family, implying that such protein-protein interaction may play a role in apical localization of the transporters. Among the PDZ proteins, PDZK1 is colocalized on apical membranes in kidney and small intestine with OCTN2, and can stimulate transport activity of several transporters including OCTN1, OCTN2 and PEPT2. Finally, we have focused on functional modulation of oligopeptide transporter PEPT1 by Na^+/H^+ exchanger (NHE) 3 that can also bind to the PDZ proteins and supply H^+ gradient that can be utilized by PEPT1 for transport activity. NHE3 affects transport activity, Na^+- and H^+- dependence of PEPT1. Thus, this study has proposed a novel concept that adaptor proteins (such as PDZK1) and other membrane proteins (such as NHE3), both having interaction potential with transporters, could be important molecular basis for prediction of drug-drug interaction at excretion processes.
|
Report
(3 results)
Research Products
(18 results)
-
[Journal Article] Carrier-mediated hepatic uptake of a novel non-renal excretion type uric acid generation inhibitor, Y-700.2006
Author(s)
Sai Y, Kato Y, Nakamura K, Kato S, Nishimura T, Kubo Y, Tamai I, Yang S, Hu Z, Yamada I, Tsuji A
-
Journal Title
J Pharm Sci 95・2
Pages: 336-347
Description
「研究成果報告書概要(和文)」より
Related Report
-
-
[Journal Article] Carrier-mediated hepatic uptake of a novel non-renal excretion type uric acid generation inhibitor, Y-700.2006
Author(s)
Sai Y, Kato Y, Nakamura K, Kato S, Nishimura T, Kubo Y, Tamai I, Yang S, Hu Z, Yamada I, Tsuji A
-
Journal Title
J Pharm Sci. 95(2)
Pages: 336-347
Description
「研究成果報告書概要(欧文)」より
Related Report
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
