| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
To define the influence of drug-metabolizing enzyme CYP2C9-polymorphism on therapeutic significance, we investigated the metabolism of fluvastatin (FL), an HMG-CoA reductase inhibitor, in human B-lymphoblastoid cells-expressed CYP2C9*1 or baculo virus-expressed human CYP2C9*3 in vitro. Furthermore, we studied the relationship between CYP2C9-polymorphism and therapeutic effects of FL or its pharmacokinetic (PK) and/or pharmacodynamic (PD) alterations in the patients with hypercholesterolemia or healthy subjects. In vitro study with human lymphoblastoid cells-expressed CYPs demonstrated that the reactions from FL to 5-hydroxy FL (M2) and to desisopropyl FL (M5) were catalyzed specifically by CYP2C9, but the formation of 6-hydroxy FL (M3) was catalyzed by both of CYP2C9 and CYP3A4. Furthermore, the in vitro data suggested that the formation of desisopropyl-2-propionic acid FL (M4) was catalyzed mainly by CYP2E1 rather than CYP2C9. On the other hand, the formation rates (Vmax/Km) of M2, M4
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and M5 decreased by more than 60 % in CYP2C9*3/*3, compared with CYP2C9*1/*1. The formation of M3 was not detected in CYP2C9*3. The effects of CYP2C9 -polymorphism on both of PK and/or PD of FL were assessed in healthy subjects with a single administration of 20 mg of FL or in the patients with hypercholesterolemia during the consecutive administrations of 20 mg/day of FL for 6 months. The alterations of PK and/or PD of FL in the patients and the healthy subjects with CYP2C9*1/*3 were not found significantly, compared with those in the patients and the healthy subjects with CYP2C9*1/*1, Plasma levels of M3 and M5 in CYP2C9*1/*3 group decreased by more than 50 %, compared with CYP2C9*1/*1 group, but that of M4 in the former increased up to about 2 times that of the later. These results suggested that although the formations of M3 and M5 decreased in the patients with CYP2C9*1/*3, the lack of alterations in PK and PD of FL in them may result from the compensation of CYP2E1 for the formation of M4. Less
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