Multiple analysis concerning therapeutic significance of drug-metabolizing enzyme CYP2C9 polymorphism

为了确定药物代谢酶CYP2C9多态性对治疗意义的影响，我们研究了HMG-CoA还原酶抑制剂氟伐他汀（FL）在体外表达CYP2C9*1的人b淋巴母细胞样细胞和杆状病毒表达的人CYP2C9*3中的代谢。此外，我们还研究了cyp2c9多态性与高胆固醇血症患者或健康受试者的FL治疗效果或其药代动力学（PK）和/或药效学（PD）改变之间的关系。体外对表达CYPs的人淋巴母细胞的研究表明，从FL到5-羟基FL （M2）和去异丙基FL （M5）的反应是由CYP2C9特异性催化的，而6-羟基FL （M3）的形成是由CYP2C9和CYP3A4共同催化的。此外，体外数据表明，去异丙基-2-丙酸FL （M4）的形成主要由CYP2E1而不是CYP2C9催化。另一方面，在CYP2C9*3/*3中，M2、M4、More和M5的形成速率（Vmax/Km）比CYP2C9*1/*1降低60%以上。CYP2C9*3未检测到M3的形成。CYP2C9多态性对单次给药20mg FL的健康受试者和连续给药20mg /d的高胆固醇血症患者PK和/或PD的影响进行了评估。CYP2C9*1/*3组患者与健康人血浆中FL的PK和/或PD变化均未见明显变化，与患者和健康人相比，CYP2C9*1/*1组血浆中M3和M5水平比CYP2C9*1/*1组降低50%以上，而M4水平比CYP2C9*1/*1组升高约2倍。这些结果提示，CYP2C9*1/*3的患者虽然M3和M5的形成减少，但其FL的PK和PD没有改变，可能是由于CYP2E1对M4的形成进行了补偿。少

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 … More 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