同样的胆固醇合成抑制剂在人类肝细胞产生的影响在不同的细胞色素P450酶。

文章的细节

引用

复制到剪贴板

科恩LH, van Leeuwen再保险,范泰尔GC, van Pelt摩根富林明,金伟军

同样的胆固醇合成抑制剂在人类肝细胞产生的影响在不同的细胞色素P450酶。

Biopharm药物Dispos。2000年12月,21日(9):353 - 64。

PubMed ID

11523064 (在PubMed

]

文摘

六3-hydroxy-3-methylglutaryl辅酶A(β)还原酶抑制剂(目前的降胆固醇药物他汀类药物),洛伐他汀(L)、辛伐他汀,普伐他汀(P), fluvastatin (F)、阿托伐他汀(A)和cerivastatin (C)所示的胆固醇合成抑制剂在人类肝细胞,这些药物的靶组织的人。所有六个抑制纳米范围(IC(50)值:0.2 - -8.0海里)。作为日常使用降胆固醇药物可能会与其他药物coadministered。虽然几个细胞色素P450 (CYP)参与药物代谢酶在肝脏,从而发挥重要作用的药物之间的相互作用是研究这些酶受活动形式的六个他汀类药物的影响。这些人类肝微粒体酶活性进行了研究准备,猿和人类肝细胞在初级文化。以下CYP反应是使用:硝苯地平芳构化(CYP3A4),睾丸激素6 beta-hydroxylation (CYP3A4)、甲苯磺丁脲methylhydroxylation (CYP2C9) S-mephenytoin 4-hydroxylation (CYP2C19) bufuralol 1 '羟基化(CYP2D6)苯胺4-hydroxylation (CYP2E1)香豆素7-hydroxylation(体内CYP2A6基因表现)和7-ethoxyresorufin O-dealkylation (CYP1A1/2)。在人肝微粒体的他汀类药物(400 microM)浓度没有影响CYP1A1/2体内CYP2A6基因表现活动,几乎和CYP2E1的活动。除了P,其他五个他汀类药物还强的抑制剂CYP2C19活动与IC(50)值约200 microM和同样的效果,C和F CYP2D6的活动。L和S是较弱的抑制剂的酶活性,而P不影响活动。差不多是他汀类药物影响的观察CYP2C9活动,除了F是这个活动的强有力的抑制剂(IC(50)值:4 microM)。 Using the assay of testosterone 6beta-hydroxylation the CYP3A4 activity was decreased by L, S and F with IC(50) values of about 200 microM and a little more by C and A (IC(50) around 100 microM). P had hardly an effect on this activity. To a somewhat less extent the same trend was seen when CYP3A4 activity was measured using nifedipine as substrate. The inhibitory effects observed in microsomes were verified in suspension culture of freshly isolated hepatocytes from Cynomolgus monkey (as a readily available model) and of human hepatocytes. In general the same trends were seen as in the human microsomes, except that in some cases the inhibition of the CYP activity was less, possibly by the induction of the particular CYP enzyme by incubation of the cells with a particular statin. F remained a strong inhibitor of CYP2C9 activity in human and monkey hepatocytes. A induced the CYP2C9 in monkey hepatocytes but was an inhibitor of the CYP2C9 in human hepatocytes. A, S, L and C were moderate inhibitors in both cellular systems of CYP3A4. P was not affecting any of the CYP activities in the three systems studied. It is concluded that different CYP enzymes interact with different statins and therefore differences in between these drugs are to be expected when drug-drug interaction is considered.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
阿托伐他汀	细胞色素P450 2 c19	蛋白质	人类	没有	抑制剂	细节
阿托伐他汀	细胞色素P450 2 c9	蛋白质	人类	没有	抑制剂	细节
阿托伐他汀	细胞色素P450 2 d6	蛋白质	人类	没有	抑制剂	细节
阿托伐他汀	细胞色素P450 3 a4	蛋白质	人类	没有	底物	细节
Cerivastatin	细胞色素P450 2 c9	蛋白质	人类	未知的	抑制剂	细节
Cerivastatin	细胞色素P450 2 d6	蛋白质	人类	未知的	抑制剂	细节
Cerivastatin	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节
Fluvastatin	细胞色素P450 2 c19	蛋白质	人类	未知的	抑制剂	细节
Fluvastatin	细胞色素P450 2 d6	蛋白质	人类	未知的	底物	细节
辛伐他汀	细胞色素P450 2 c9	蛋白质	人类	未知的	抑制剂	细节
辛伐他汀	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节