2000 Fiscal Year Final Research Report Summary
The elucidation of cephaloridine-induced nephrotoxicity in cell lines stably expressing organic anion transporters
| Project/Area Number |
11671048
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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 |
Kidney internal medicine
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| Research Institution | Kyorin University |
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Principal Investigator |
TAKEDA Michio Kyorin Univ.Sch.Med.Dept.Pharamcol.& Toxicol.Lecturer, 医学部, 講師 (40255401)
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| Co-Investigator(Kenkyū-buntansha) |
ENDOU Hitoshi Kyorin Univ.Sch.Med.Dept.Pharamcol.& Toxicol.Professor, 医学部, 教授 (20101115)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Organic anion transporter / Cephaloridine / Nephrotoxicity / Cell line / Proximal tubule / Ochratoxin A |
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| Research Abstract |
We elucidated the role of organic anion transporter (OAT) in cephaloridine (CER)-induced nephrotoxicity using stable cell lines.
(1)Rat OAT1 and rat OAT3 mediate CER uptake and its nephrotoxicity. Rat OAT1 and rat OAT3 exhibited distinct substrate recognition against various cephalosporin antibiotics.
(2)Comparing the Ki values of hOAT1 and hOAT3 with clinically relevant plasma concentrations of various cephalosporin antibiotics, hOAT1 was shown to interact with various cephalosporin antibiotics in vivo.
(3)Rat OAT1, hOAT1 and hOAT3 were shown to mediate ochratoxin A transport and its nephrotoxicity.
(4)Various OAT inhibitors, betamipron, cilastatin, probenecid and KW-3902, were shown to inhibit CER-induced nephrotoxicity. The kinetic analysis of the inhibitory effects of these drugs was performed, and the Ki values were compared with clinically relevant plasma concentrations of these drugs. It was suggested that the molecular target of these inhibitors was hOAT1 and hOAT3 for betamipron, probenecid, and hOAT3 for cilastatin. In contrast, KW-3902 did not have any clinical impact.
(5)Molecular identity for the drug interaction between methotrexate and nonsteroidal anti-inflammatory drug was identified to be hOAT3.
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