A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane x receptor
A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane x receptor
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DOI：
10.1124/dmd.107.019547
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Kim, Richard B.
中科院分区：
文献类型：
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作者：
Healan-Greenberg, Christine;Waring, Jeffrey F.;Kim, Richard B.
药物与药物的相互作用包括诱导细胞色素P450酶(P450)，可导致药物疗效的丧失。某些药物，特别是那些用于治疗分枝杆菌和人类免疫缺陷病毒(HIV)感染的药物，特别容易诱发P450。在研究化合物在培养的人肝细胞中的药物相互作用潜力的过程中，暴露于(S)-1-[(1S，3S，4S)-4-[(S)-2-(3-benzyl-2-oxo-imidazolidin-1-yl)-3，3-dimethyl-butyrylamino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-yl-benzyl)pentylcarbamoyl]-2，2-dimethyl-propyl-carbamic酸甲酯(A-792611)，以前正在研究的用于治疗艾滋病毒感染的新型艾滋病毒蛋白酶抑制剂(PI)，导致组成性细胞色素P3A4表达显著下调。此外，A-792611的联合应用可减弱已知诱导剂利福平和伊法韦仑介导的细胞色素P3A4的诱导作用。在荧光素酶报告分析中，A-792611还减弱了利福平和利托那韦介导的人孕烷X受体(PxR)的激活。对培养的人肝细胞的芯片分析表明，A-792611处理下调了PXR靶基因CYP3A4、CYP2B6、CYP2C8和CYP2C9的表达，而在处理的大鼠肝细胞中没有观察到诱导作用。A-792611不与其他调节P450表达的配体激活的核受体相互作用，如组成性雄烷受体、法尼醇X受体、维生素D受体和过氧化物酶体增殖物激活受体α。这些数据表明，A-792611是一种功能性和有效的人类PXR抑制剂。在典型的PxR激活剂类HIV-Pls中，A-792611似乎具有PxR拮抗的独特性质，可能是研究核受体途径调控的有用工具。
Drug-drug interactions involving induction of cytochrome P450 enzymes (P450s) can lead to loss of drug efficacy. Certain drugs, particularly those used to treat mycobacterial and human immunodeficiency virus (HIV) infections, are especially prone to induce P450s. During studies to examine drug-interaction potential of compounds in cultured human hepatocytes, exposure with (S)-1-[( 1S, 3S, 4S)-4-[(S)-2-(3-benzyl-2-oxo-imidazolidin-1-yl)-3,3-dimethyl-butyrylamino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-yl-benzyl)pentylcarbamoyl]-2,2-dimethyl-propyl-carbamic acid methyl ester (A-792611), a novel HIV protease inhibitor (PI) previously under investigation for the treatment of HIV infection, resulted in significant down-regulation of constitutive CYP3A4 expression. Furthermore, coadministration of A-792611 was found to attenuate CYP3A4 induction mediated by known inducers rifampin and efavirenz. A-792611 also attenuated the rifampin and ritonavir-mediated activation of the human pregnane X receptor (PXR) in luciferase reporter assays. Microarray analysis on cultured human hepatocytes revealed that A-792611 treatment down-regulated the expression of PXR target genes CYP3A4, CYP2B6, CYP2C8, and CYP2C9, whereas there was a lack of inductive effect observed in treated rat hepatocytes. A-792611 did not interact with other ligand-activated nuclear receptors that regulate P450 expression such as constitutive androstane receptor, farnesoid X receptor, vitamin D receptor, and peroxisome proliferator-activated receptor alpha. These data suggest that A-792611 is a functional and effective human PXR inhibitor. Among the class of HIV-Pls, which are typically PXR activators, A-792611 seems to have a unique property for PXR antagonism and could be a useful tool for studying nuclear receptor pathway regulation.