CYP3A4 Induction by Xenobiotics: Biochemistry, Experimental Methods and Impact on Drug Discovery and Development

CYP3A4型 异型生物质的 生物 孕烷X受体 药物代谢 药理学 药物发现 细胞色素P450 药品 骨化三醇受体 报告基因 化学 雄激素受体 CYP2B6型 计算生物学
作者
Gang Luo,Thomas M. Guenthner,Liang‐Shang Gan,W. Griffith Humphreys
出处
期刊:Current Drug Metabolism [Bentham Science]
卷期号:5 (6): 483-505 被引量:142
标识
DOI:10.2174/1389200043335397
摘要

Cytochrome P450 3A4 (CYP3A4), an enzyme that is highly expressed in the human liver and small intestine, plays a major role in the metabolism of a large variety of xenobiotics, including an estimated 50% of therapeutic drugs, as well as many endogenous compounds. The expression of CYP3A4 can be induced by xenobiotics. Such induction leads to accelerated metabolism of the xenobiotics themselves (autoinduction) or of concomitantly administered CYP3A4 substrates/drugs, thereby significantly altering their pharmacokinetic and pharmacodynamic profiles. During the past decade, much progress has been made in our understanding of the biological mechanisms responsible for regulation of CYP3A4 expression. It is now known that many xenobiotics induce CYP3A4 expression via the pregnane X receptor (PXR) pathway, while others are thought to act through the constitutive androstane receptor (CAR) and the vitamin D receptor (VDR). As a result, most pharmaceutical companies have recognized that it is important to evaluate CYP3A4 induction potential preclinically and are using primary cultures of human hepatocytes and/or PXR reporter gene assays. In general, the results from these two assay methods correlate well. The reporter gene assays in particular can be used to rapidly screen hundreds of drug candidates, whereas methods using primary human hepatocyte cultures may more accurately assess the potential for CYP3A4 induction in vivo. Although it is important to consider CYP3A4 induction in the early stages of the drug development process, it should be recognized that the assessment of induction potential preclinically is a difficult and imprecise endeavor and can be complicated by many factors.
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