1992 Fiscal Year Final Research Report Summary
Scientific Basis of Drug Disposition in the Kidney and its Application to Clinical Dosage Regimens.
| Project/Area Number |
03454488
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
HORI Ryohei Kyoto Univ., Medicine, Professor, 医学部, 教授 (40001036)
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| Co-Investigator(Kenkyū-buntansha) |
HE Yan-ling Kyoto Univ. Med. Instructor, 医学部, 助手 (70233640)
TAKANO Mikihisa Kyoto Univ. Med. Lecturer, 医学部, 講師 (20211336)
TANIGAWARA Yusuke Kyoto Univ. Med. Lecturer, 医学部, 講師 (30179832)
YASUHARA Masato Kyoto Univ. Med. Assoc. Prof., 医学部, 助教授 (00127151)
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| Project Period (FY) |
1991 – 1992
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| Keywords | Renal excretion / Gene transfection / P-glycoprotein / Isolated perfused kidney / Population pharmacokinetics / Dosage regimen |
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| Research Abstract |
The kidney is a major organ for the excretion of xenobiotics, and is of critical importance in the pharmacokinetics. In the present study, we examined the structure and the regulatory mechanisms of the anionic, cationic, amphoteric and nonionic drug transport system, utilizing the renal plasma membrane vesicles, the cultured kidney epithelial cell, and the isolated perfused kidney. In addition, we developed the new strategy to design clinical dosage regimens by use of the basic information on the drug disposition in the kidney.
1. Utilizing the rat isolated perfused kidney, we demonstrate that the basolateral membrane transport is a determining step in transepithelial transport of p-aminohippurate in renal tubular secretion.
2. The kidney epithelial cell line LLC-PK_1 can transport procainamide by the organic cation transport system, and procainamide in transported unidirectionally from basolateral to apical side across the cell monolayer. In addition, we demonstrated that the renal organic cation transporter was expressed in Xenopus leavis oocytes and that a 1.4-2.4 kb poly(A)^+ RNA fragment expressed the transporter.
3. Human P-glycoprotein was expressed on the apical membrane of porcine kidney epithelial cell line, LLC-PK_1. Digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney.
4. Therapeutic drug monitoring data from the routine patient care were analyzed by the population pharmacokinetic approach. The covariates influencing the drug disposition could be evaluated by the clinical test data. We demonstrated the Bayesian inference method based on the population pharmacokinetic parameters is useful for the dose-adjustment in individual patients.
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