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

为了明确药物代谢酶CYP 2C 9-多态性对治疗意义的影响，我们研究了氟伐他汀（FL），一种HMG-CoA还原酶抑制剂，在人B淋巴母细胞表达的CYP 2C 9 *1或杆状病毒表达的人CYP 2C 9 *3体外代谢。此外，我们研究了CYP 2C 9-多态性与FL的治疗效果或其药代动力学（PK）和/或药效学（PD）的改变在高胆固醇血症患者或健康受试者之间的关系。用人淋巴母细胞表达的CYP进行的体外研究表明，从FL到5-羟基FL（M2）和去异丙基FL（M5）的反应由CYP 2C 9特异性催化，但6-羟基FL（M3）的形成由CYP 2C 9和CYP 3A 4催化。此外，体外数据表明，去异丙基-2-丙酸FL（M4）的形成主要由CYP 2 E1而非CYP 2C 9催化。另一方面，M2、M4的形成速率（Vmax/Km） ...更多信息 与CYP 2C 9 *1/*1相比，M5在CYP 2C 9 *3/*3中降低超过60%。在CYP 2C 9 *3中未检测到M3的形成。在健康受试者单次服用20 mg FL或高胆固醇血症患者连续服用20 mg/天FL 6个月期间，评估CYP 2C 9-多态性对FL PK和/或PD的影响。与CYP 2C 9 *1/* 1患者和健康受试者相比，CYP 2C 9 *1/*3患者和健康受试者中FL的PK和/或PD未发现显著变化，CYP 2C 9 *1/*3组的M3和M5血浆水平较CYP 2C 9 *1/*1组降低50%以上，而M_4在前者中的含量则增加到后者的2倍左右。这些结果表明，虽然在CYP 2C 9 *1/*3患者中M3和M5的形成减少，但他们中FL的PK和PD没有改变，可能是由于CYP 2 E1对M4形成的补偿。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