| Project/Area Number |
11672139
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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 |
Physical pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
SHIBUKAWA Akimasa Kyoto University, Graduate school of pharmaceutical sciences, Associate professor, 薬学研究科, 助教授 (30170913)
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| Co-Investigator(Kenkyū-buntansha) |
KURODA Yukihiro Kyoto University, Graduate school of pharmaceutical sciences, Associate professor, 薬学研究科, 助手 (60314225)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | lipoprotein / binding analysis / capillary electrophoresis / frontal analysis / LDL / nilvadipine / flvastatin / liposome / リポタンパク / 血漿リポタンパク質 / 低密度リポタンパク質 |
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| Research Abstract |
Hydrophobic drugs and basic drugs are bound to plasma lipoproteins, which gives significant effect upon drug disposition and pharmacodynamics. Low-density lipoprotein (LDL) suffers from in vivo oxidation. This oxidative modification may affect the drug binding ability, resulting in the change in the pharmacokinetic property. Some components of LDL such as apolipoproteins are chiral compounds. Therefore, binding of a chiral drug to LDL may be enantioselective. In this study, the effect of LDL oxidationt upon the binding between LDL and chiral drugs were investigated quantitatively and enantioselectively by using our original method, high-performance frontal analysis/capillary electrophoresis (HPFA/CE). The following results were found.
1) The oxidative modification of LDL enhanced the binding of model drugs such as verapamil, nilvadipine and fluvastatin (antihyperlipidemia). The nK value of fluvastatin was increased by two-fold after 2-hr LDL oxidation.
2) The binding of model drugs to oxidized LDL is non-specific and partition like binding. The bound drug fraction is constant regardless of the total drug-concentration. No enantioselectivity was found in the drug oxidized LDL binding.
3) In order to estimate the contribution of oxidation of LDL lipid components, several model liposomes containing different acyl-chain structure or different net charge were prepared, and their binding property with model basic drugs (verapamil and propranolol) was investigated. It was found that the decrease of positive net charge during LDL oxidation plays the most effective role in the enhancement of drug binding affinity. The change in acyl-chain structure is less effective than the change in the net charge.
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