细胞色素P450酶系在药物代谢中的作用

该文从细胞色素P450概述、参与药物代谢的人类细胞色素P450亚型、细胞色素P450与药物的相互作用、细胞色素P450多态性在药物不良反应中的作用及细胞色素P450酶系产生药物不良反应的机制等方面综述细胞色素P450酶系对药物代谢的影响，为指导临床合理用药，避免药物不良反应及个体化用药提供参考。     

中成药对细胞色素P450酶的影响

通过参阅大量近年来国内外有关中成药对药物代谢酶细胞色素P450酶影响的文献,对中成药对细胞色素P450酶的研究的文献进行整理和分析.发现一些中成药对细胞色素P450酶确实存在不同程度的抑制或诱导作用.因此深入研究中成药对细胞色素P450酶活性的影响,既有助于指导中成药在临床上的合理使用以避免因药物相互作用导致的不良反应...     

细胞色素P450酶系与药物代谢的相互作用

药物在体内代谢,不论是哪一种方式,都有酶的参与.与药物代谢关系最大的是细胞色素P450酶系,它主要存在于人体肝脏的微粒体中,故也称为肝微粒体酶,细胞色素酶是一种以铁卟啉为辅基的蛋白质(cytochrome protein),属于b族细胞色素,因还原型P450与一氧化碳的复合物P450-CO在450 nm处有一强吸收峰,故而得名细胞色素P450[1].该酶有许多同工酶,故称细胞色素P450酶系,简称为CYP450S.     

反应中间产物和代谢物的形成——大环内酯抗生素对细胞色素P450作用

许多外来物对体内依赖于单氧酶的细胞色素P450有多种作用,这对研究药物相互作用有重要意义.下图简示药物相互作用.一药物R'H阻碍细胞色素P450活性,从而使药物RH的血浆水平和治疗效应起显著变化.     

细胞色素P450酶在癌症研究中的应用

细胞色素P450酶是体内代谢转换的重要酶系.现从细胞色素P450酶在活性调节、代谢表型、致癌 物活化、抗癌药物代谢、肿瘤组织中特异表达和肿瘤基因治疗等方面综述细胞色素P450酶的特点及其在癌症研究中的应用潜力.     

细胞色素P450酶的时间依赖性抑制研究及其在新药研发中的作用

细胞色素P450酶介导绝大多数药物的体内代谢,有些临床药物相互作用问题是由于药物对细胞色素P450酶的时间依赖性抑制引起的,但在传统的体外抑制筛选方法中并未包括对时间依赖性抑制的评价方案。本文综述了药物时间依赖性抑制的研究意义及评价方法 (包括单点抑制法、IC50shift筛选法、酶动力学实验法等),并介绍如何利用所得体外数据进行临床预测。     

与细胞色素P450亚型酶代谢相关的药物

细胞色素P450（CYP450）是人体内广泛存在的、具有复杂功能的酶系统,是药物代谢的主要途径。本文主要介绍用于细胞色素P450亚型酶的代谢底物及其诱导剂、抑制剂等,为研究药物在体内的代谢提供基础,指导临床合理用药。     

细胞色素P450酶系和药物的不良反应

细胞色素P450酶系在药物代谢中扮演了重要角色.本文描述了许多环境的和基因的因素,这些因素调整人体酶和它们的药物底物的活性.在一些情况下,细胞色素P450酶具有基因的多态性,导致对某些药物在表型上明显慢和明显快的代谢.慢代谢者(PMs)易发生与浓度相关的药物不良反应,而快代谢者(EMs)则对药物相互作用易感;其中抑制的相互作用可能会由于血浆浓度的增加而导致毒性.药物代谢被改变是药物不良反应的重要原因.     

P450酶介导的EGFR-TKIs药物与其他药物的相互作用

目的 探讨细胞色素P450酶介导的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)与其他药物的相互作用.方法 查阅文献,统计国家药品监督管理局批准用于治疗晚期非小细胞肺癌的7个EGFR-TKIs与P450酶相关的药物相互作用.结果 7个EGFR-TKIs中,阿法替尼的代谢不经过P450酶途径,也并非CYP酶系的诱...     

兰索拉唑药动学和药物相互作用的研究进展

兰索拉唑为苯并咪唑类衍生物,主要通过抑制H+ K+ ATP酶而发挥抗酸作用,在体内主要经细胞色素P450(CYP)2C19和CYP3A4代谢,酶在不同人群中的差异造成了其体内代谢的个体差异.同时,兰索拉唑有两个立体异构体,两者在体内的代谢也有差异.兰索拉唑经酶代谢会导致与其他经同样酶代谢的药物发生相互作用.该文综述了兰索拉唑的药动学和与其他药物相互作用,及其联合用药的研究进展.     

Inhibition of Cytochrome P450 Enzymes by Drugs—Molecular Basis and Practical Applications

Drug-drug interactions are a major cause of hospitalization and deaths related to drug use. A large fraction of these is due to inhibition of enzymes involved in drug metabolism and transport, particularly cytochrome P450 (P450) enzymes. Understanding basic mechanisms of enzyme inhibition is important, particularly in terms of reversibility and the use of the appropriate parameters. In addition to drug-drug interactions, issues have involved interactions of drugs with foods and natural products related to P450 enzymes. Predicting drug-drug interactions is a major effort in drug development in the pharmaceutical industry and regulatory agencies. With appropriate in vitro experiments, it is possible to stratify clinical drug-drug interaction studies. A better understanding of drug interactions and training of physicians and pharmacists has developed. Finally, some P450s have been the targets of drugs in some cancers and other disease states.     

Microsomal monooxygenase as a multienzyme system: the role of P450-P450 interactions

INTRODUCTION: There is increasing evidence of physical interactions (association) among cytochromes P450 in the membranes of the endoplasmic reticulum. Functional consequences of these interactions are often underestimated. AREAS COVERED: This article provides a comprehensive overview of available experimental material regarding P450-P450 interactions. Special emphasis is given to the interactions between different P450 species and to the functional consequences of homo- and heterooligomerization. EXPERT OPINION: Recent advances provide conclusive evidence for a substantial degree of P450 oligomerization in membranes. Interactions between different P450 species resulting in the formation of mixed oligomers with altered activity and substrate specificity have been demonstrated clearly. There are important indications that oligomerization impedes electron flow to a fraction of the P450 population, which renders some P450 species nonfunctional. Functional consequences of P450-P450 interactions make the integrated properties of the microsomal monooxygenase remarkably different from a simple summation of the properties of the individual P450 species. This complexity compromises the predictive power of the current in vitro models of drug metabolism and warrants an urgent need for development of new model systems that consider the interactions of multiple P450 species.     

CYP450与药物相互作用

目的 探讨细胞色素P450（CYP450）与药物相互作用的关系.方法 检索国内外数据库中与药物相互作用的相关文献,并查阅相关书籍,总结CYP450酶与药物相互作用的关系.结果 CYP450与药物相互作用关系最密切的是酶系统,凡参与代谢的酶都与药物相互作用有关,其中最主要的是CYP1 A2,2C9,2C19,2D6,3A4.结论 充分了解药物的药理及药代动力学特点,当与可能发生相互作用的药物合用时,应密切监测患者的情况,必要时进行药物剂量调整或换用其他药物.     

Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms

The cytochrome P450s are responsible for about 75% of phase I dependent drug metabolism and for the metabolism of a huge amount of dietary constituents and endogenous chemicals. The human has 59 active genes, and 6 of those encode important drug metabolising enzymes. About 40% of cytochrome P450 dependent drug metabolism is catalysed by polymorphic enzymes and such drug P450 interactions are frequently seen in adverse drug reaction reports. In this contribution an update of human cytochrome P450 enzymology and pharmacogenetics is given with particular emphasis on CYP1B1, CYP2B6, CYP2E1 and CYP3As.     

“cocktail”探针药物法及其在研究中药对细胞色素P450影响中的应用进展

"cocktail"(鸡尾酒)探针药物法作为一种快速、高通量的研究方法,目前已广泛应用于药物对细胞色素P450(CYP450)活性影响评估、药物代谢途径确认、药物-药物相互作用预测、药物代谢表型分析、临床用药方案优化等诸多研究方向。此方法具有独特的优势和广阔的应用前景。本文主要从CYP450同工酶的特性、"cocktail"探针药物法的特点、探针药物选择依据、"cocktail"探针药物法在中药对CYP450代谢酶影响中的应用进行综述。旨在较为系统地梳理相关研究进展,并为此方面的深入研究工作提供参考。     

Inhibition and induction of cytochrome P450 2B1 in rat liver by promazine and chlorpromazine.

Phenothiazine tranquilizers have been associated with pharmacokinetic drug interactions in man. In this study the in vivo and in vitro effects of the clinically important phenothiazines promazine (PZ) and chlorpromazine (CPZ) on drug oxidations catalysed by specific cytochrome P450 (P450) enzymes were investigated in the rat. In vitro, the two drugs were relatively ineffective inhibitors of constitutive P450 activities, but were inhibitory toward the principal phenobarbital-inducible P450 2B1 and, to a lesser extent, P450 1A1. Administration of PZ and CPZ to male rats did not markedly influence the total microsomal P450 content of the liver. However, the quantitatively important male-specific P450 2C11 was down-regulated by CPZ and concomitant induction of P450 2B1 and associated 7-pentylresorufin O-depentylase activity were noted. A small increase in the activity of microsomal 7-ethylresorufin O-deethylase was also observed following administration of both drugs to rats, suggesting induction of P450 1A1/2. Considered together, it is apparent that the two phenothiazines are preferential inhibitors and inducers of P450 2B1 in rat liver. Drug interactions in humans involving phenothiazines may reflect a combined effect of induction and inhibition processes as well as down-regulation of other P450s, such as that produced by CPZ on P450 2C11.     

细胞色素P450与外源物的相互作用研究进展

细胞色素P450酶是一种多功能酶系,它既参与外源物的生物转化,也与内源性物质的代谢有关,并且作为肝细胞药物代谢的主要酶系参与药物毒性的代谢灭活。由于P450酶结构、功能和基因调控的多样性,自其发现以来,该酶系的研究一直是毒理学研究中的一个热点。本文综述了P450与药物代谢相关的主要亚型及其与药物的相互作用,探讨了P450酶与外源物代谢之间的相互作用机制。     

Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo condition.

For the most part, the majority of adverse drug-drug interactions, which are pharmacokinetic in origin, can be understood in terms of alterations of cytochrome P450-catalyzed reactions. Much is known about the human P450 enzymes, and in many cases it is possible to apply this information to clinically related issues. Of the relatively small subset of the total number of human P450s, CYP3A4 appears to be responsible for the largest fraction of the drug oxidation reactions. As a consequence many important drug-drug interactions observed in the clinic are associated with drugs which are principally metabolized by CYP3A4. The two major reasons for drug-drug interactions involving CYP3A4 are induction and inhibition, with inhibition appearing to be the more important in terms of known clinical problems. Fortunately, with the available knowledge of human P450s and in vitro reagents, it is possible to do experiments with drugs to predict the in vivo condition. The goal of these studies is not only to improve predictions about which drugs might show serious P450 interaction problems, but also to decrease the number of in vivo interaction studies that must be performed in drug development. The focus of the current report is to describe some of the confounding factors associated with in vitro drug inhibition studies and the impact of these issues on in vitro/in vivo extrapolations.     

Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19.

Hybridomas were isolated that produce 13 monoclonal antibodies (mAbs) that are specific and highly inhibitory to members of the human P450 2C subfamily, 2C8, 2C9, 2C9*2, and 2C19. Many of the mAbs to P450 2C8, 2C9, and 2C19 are specific and exhibit potent inhibitory activity (85-95%). mAb 281-1-1 specifically binds, immunoblots, and strongly inhibits the activity of P450 2C8. mAb 763-15-5 specifically binds and strongly inhibits the activity of P450 2C9. mAb 1-7-4-8 specifically binds and strongly inhibits the activity of P450 2C19. The other mAbs bind and inhibit sets and subsets of the P450 2C family. The single and the combinatorial use of the mAbs can "reaction phenotype", i.e., determine the metabolic contribution and interindividual variation of a P450 isoform for the metabolism of a drug or nondrug xenobiotic in human liver microsomes. The utility of the mAb-based analytic system was examined with the model substrates Taxol (paclitaxel), diazepam, tolbutamide, diclofenac, mephenytoin, and imipramine. The mAb system can identify drugs metabolized by a common P450 or several P450s and polymorphic P450s. The mAb system identifies drugs or drug metabolic pathways that are catalyzed by a single P450 and thus may be used for in vivo phenotyping. The mAb system can identify whether a particular drug is metabolized by a single P450 that may exhibit polymorphic expression in humans. The mAb system offers large potential for studies of cytochrome P450 function useful in drug discovery and reduces the possibility of adverse drug reactions due to polymorphisms and drug interactions.     

Cocktail法研究CYP450酶活性影响因素的探讨

细胞色素P450酶(cytochrome P450, CYP450)是药物代谢的重要酶系,研究CYP450对阐明药物代谢通路、相互作用、代谢多态性、指导临床合理用药等方面具有重要意义.混合探针底物法(Cocktail法)在研究CYP450亚型酶活性应用广泛,具有高效、准确、灵敏、高通量的特点.但CYP450亚型酶存在种属差异、性别差异、探针药物的特异性等方面的问题.查阅国内外相关文献,探讨Cocktail法研究CYP450酶活性的影响因素.