细胞色素P4502D6基因多态性和药物相互作用

细胞色素P4502D6（CYP2D6）是一种重要的P450系氧化代谢酶,参与多种重要药物的代谢.CYP2D6具有基因多态性,对药物的代谢呈现明显的个体差异.而且CYP2D6能被多种药物竞争性抑制和诱导,药物联用时易产生相互作用.本文从CYP2D6的基因多态性与代谢表型、底物竞争作用、代谢酶的诱导和抑制等方面,探讨CYP2D6基因多态性与药物相互作用的关系.     

细胞色素P450 2D6、3A4和19A1基因多态性与乳腺癌的药物治疗

细胞色素P450(CYP)是一种重要的氧化代谢酶,参与多种药物的代谢。CYP酶具有基因多态性,对药物的代谢呈现明显的差异,对乳腺癌用药也有差异性影响。该文主要阐述细胞色素P450 2D6、3A4和19A1亚型的多态性,并就其多态性对临床乳腺癌治疗中重要的药物如他莫昔芬、芳香化酶抑制剂、紫杉醇类在治疗学方面的影响进行综述。     

细胞色素P4502D6与药物代谢

细胞色素P4502D6（CYP2D6）是一种重要的P450系氧化代谢酶,除参与代谢一些内源性物质和某些环境中毒性化合物外,主要是参怀多种重要药物的代谢,如作用于心血管和中枢神经系统的药物。CYP2D6参与代谢的药物占总P450代谢药物的30％,同时对手性药物的代谢还呈现立体选择性。研究还发现CYP2D6对药物的代谢呈现明显的个体和种族差异,引起这种差异的主要原因是CYP2D6具有的基因多态性,此外还有一些非基因因素,如药物的影响等。目前,CYP2D6的生物学特征已被基本确定,这将十分有助于对CYP2D6的深入研究,从而为临床合理用药提供科学依据。     

CYP2D6基因多态性及对美托洛尔代谢的影响

CYP2D6是一种重要的P450系氧化代谢酶,主要参与多种重要药物的代谢。CYP2D6基因多态性会引起药物代谢有显著的个体和种族差异。美托洛尔为选择性β1受体阻滞剂,临床应用上存在巨大个体差异,主要在肝脏经多条途径代谢,大约70%的代谢由CYP2D6介导,CPY2D6基因多态性对美托洛尔代谢有较大影响。本文从CYP2D6的基因多态性及它对美托洛尔代谢的影响这两方面作一综述。     

CYP2C9、CYP2C19、CYP3A4基因多态性对磺脲类降糖药代谢的影响

磺脲类口服降糖药在人体内主要经过肝脏代谢。肝脏中的细胞色素氧化酶P450是一种重要的药物代谢酶系统,在人群中存在基因多态性,导致药物疗效和不良反应在个体间存在着较大的差异。本文将对CYP450中的几种重要的代谢酶亚型CYP2C9、CYP2C19、CYP3A4的基本结构、基因多态性、种族差异及其对磺脲类降糖药代谢的影响作一综述。     

CYP450酶特性及其应用研究进展

细胞色素P450（CYP450）是药物和其他内、外源物的主要代谢酶,本文综述了人体内参与药物代谢的几种主要代谢酶CYP3A4、CYP2D6、CYP2C9、CYP2C19、CYP2E1、CYP1A2和CYP2A6的分子生物学特征,中药对药物代谢酶的影响及药物代谢酶在临床药物治疗和新药研究过程中的应用。     

与细胞色素P_(450)2D6相关的药物相互作用研究

细胞色素P450（CYP）是一组结构和功能相关的超家族基因编码同工酶。人体内参与药物代谢的CYP有17个基因家族，42个亚家族，64个酶。众所周知，在人体内许多因素如遗传因素、年龄、性别、疾病和环境都可以影响CYP的活性。本文着重综述了近年来国内、外文献报道的与CYP2D6相关的药物相互作用。CYP2D6是一种重要的细胞色素药物代谢酶，除参与代谢一些内源性物质和某些环境中毒性化合物外，主要是参与多种药物的代谢。CYP2D6参与代谢的药物占总CYP代谢药物的30％，同时对手性药物的代谢还呈现立体选择性。CYP2D6是临床上重要的肝药酶之一，与之相关的药物相互作用也十分多见。了解CYP2D6的底物以及相关的药物相互作用对临床合理用药具有十分重要的意义。     

药物代谢酶家族中CYP2D6在酿酒酵母中的表达

细胞色素P450酶（cytochrome P450,CYP）主要存在于肝微粒体中,在外源性化合物（包括药物和毒物）的生物转化中起着重要的作用,它的活性决定药物的代谢速率,与药物的清除率有着直接关系,因而又称药物代谢酶。主要有CYP1、CYP2和CYP3三大家族,其中成员CYP2D6参与降压药物、     

细胞色素P450基因多态性与药物代谢研究进展

细胞色素P450酶(cytochrome P450,CYP450)是参与人类药物代谢过程的重要酶,在肝细胞和小肠上皮细胞的光滑内质网中含量丰富,其主要功能是氧化还原各种内源性物质和外源性物质。CYP450酶参与80%目前应用药物的I相代谢,参与各种激素合成,影响与激素相关的肿瘤疾病发展。CYP450基因和表型存在高度多态性,体现在个体对于各种物质的代谢存在明显差异。本文综述了CYP450的基因多态性、与药物代谢相关的CYP450各亚型特点和临床意义,对发展以指导个体化用药为基础的精准医学具有重要意义。     

去甲替林及其代谢产物的分析

细胞色素P450 2D6(Cytochrome P450 2D6,CYP2D6)多态性已被广泛深入研究.欧洲白人发现有6%～8%的该酶慢代谢者[1],亚洲人中约有1%的该酶慢代谢者[2].慢代谢者是由于其酶缺陷等位基因造成表达产物缺陷所致的.CYP2D6参与50多种药物的代谢,其中十几种是抗抑郁药物[3].抗抑郁药物在临床使用中产生副作用的报道较多.由于产生副作用的机理不明,     

植物成分与细胞色素P450相互作用的研究进展

细胞色素P450（CYP450）是体内参与药物代谢的重要酶系,其活性在受到诱导或抑制后将干扰药物的作用。植物成分普遍存在于食物与药物中,与CYP450的相互作用将产生广泛影响。总结近年来植物成分与细胞色素P450的7个亚型CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4相互作用的研究结果,为临床上合理用药提供参考。     

植物成分与细胞色素P450相互作用的研究进展

细胞色素P450（CYP450）是体内参与药物代谢的重要酶系,其活性在受到诱导或抑制后将干扰药物的作用。植物成分普遍存在于食物与药物中,与CYP450的相互作用将产生广泛影响。总结近年来植物成分与细胞色素P450的7个亚型CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4相互作用的研究结果,为临床上合理用药提供参考。     

Genetic polymorphism of cytochrome P450 enzymes in Asian populations: focus on CYP2D6

Published studies demonstrate that significant ethnic differences can exist in the metabolism of some drugs. These differences are caused by cytochrome P450 polymorphisms and result in the potential for wide interpatient and interethnic variability in adverse events. One of the most common of these cytochrome P450 polymorphisms is related to the CYP2D6 isozyme. Many classes of commonly used drugs are metabolized by CYP2D6, creating the potential for significant adverse events. Due to the variety of genetic polymorphisms among Asian populations, this article focuses on this group rather than on other ethnic populations and discusses the clinical importance of genetic polymorphisms with regard to potential drug interactions. Polymorphism of CYP2D6 can either increase the rate of drug elimination (ultrametabolizers, leading to faster metabolic clearance potentially resulting in reduced effectiveness and need for higher doses) or decrease drug metabolism (poor metabolizers, which may increase the potential for drug interactions and adverse events). Although the CYP2D6 poor metabolizer phenotype is less frequent in Asian than in Western populations (e.g. about 1% in Thai, Chinese and Japanese populations and up to 4.8% in Indians versus 5-10% in Caucasians), the increased prevalence of the CYP2D6*10 allele in Asians does have an impact on drugs metabolized by CYP2D6. Enzyme activity is reduced, potentially increasing circulating drug doses and increasing the risk for drug interactions. Thus, in Asian populations it may be important to optimize pharmacotherapy either by assessing patients' CYP2D6 genotype, or by prescribing medications that are not metabolized by this isozyme.     

In vitro studies on quetiapine metabolism using the substrate depletion approach with focus on drug-drug interactions

The metabolism of the atypical antipsychotic quetiapine was investigated by in vitro methods. Pharmacokinetic parameters were determined in human liver microsomes and recombinant cytochrome P450 measuring substrate depletion and product formation. The cytochrome P450 isozymes CYP3A4 and CYP2D6 displayed activity towards quetiapine. The isozyme CYP2D6 played a minor role in the metabolism of quetiapine as CYP3A4 contributed 89% to the overall metabolism. A Km value of 18 microM was determined by substrate depletion, suggesting linear kinetics under therapeutic conditions. Drugs known to inhibit CYP3A4, such as ketoconazole and nefazodone, displayed almost complete inhibition at low concentrations, whereas inhibitors of CYP2D6 do not seem to have a clinically relevant effect.     

Involvement of cytochrome P450 in the metabolism of rebamipide by the human liver

1. The metabolism of rebamipide, a gastroprotective agent, was investigated using human liver microsomes and cDNA-expressed human cytochrome P450 systems. 2. 6-Hydroxy and 8-hydroxyrebamipide were produced by human cytochrome P450 enzyme(s), and 8-hydroxylation was the major metabolic pathway. K(m) and V(max) for 8-hydroxylation were 1.35 +/- 0.20 mM and 0.32 +/- 0.34 nmol min(-1) mg protein(-1), respectively (mean SD, n = 6). Kinetic analysis showed that the 8-hydroxylation reaction consisted of a single component. 3. 8-Hydroxylation was inhibited by the addition of CYP3A4 antibodies as well as troleandomycin, a specific inhibitor of CYP3A4. Furthermore, the metabolism of rebamipide in human liver microsomes was compatible with that in a human cDNA-expressed CYP3A4 system, but not for other human P450 expression systems. It is therefore suggested that the hydroxylation of rebamipide only involves CYP3A4. 4. Rebampide showed no inhibitory effect on CYP1A2-, 2C9-, 2C19-, 2D6-, 2E1- and 3A4-catalysed metabolism. In addition, the metabolic contribution by CYP3A4 was considered to be slight for the overall elimination of rebamipide in man. It is therefore considered that drug interactions with cytochrome P450 enzymes are not involved in either the metabolism of rebamipide or the metabolism of other drugs concomitantly administered with rebamipide.     

Involvement of cytochrome P450 in the metabolism of rebamipide by the human liver

1. The metabolism of rebamipide, a gastroprotective agent, was investigated using human liver microsomes and cDNA-expressed human cytochrome P450 systems. 2. 6-Hydroxy and 8-hydroxyrebamipide were produced by human cytochrome P450 enzyme(s), and 8-hydroxylation was the major metabolic pathway. K m and V max for 8-hydroxylation were 1.35 ± 0.20 mM and 0.32 ± 0.34 nmol?min -1?mg protein -1, respectively (mean SD, n = 6). Kinetic analysis showed that the 8-hydroxylation reaction consisted of a single component. 3. 8-Hydroxylation was inhibited by the addition of CYP3A4 antibodies as well as troleandomycin, a specific inhibitor of CYP3A4. Furthermore, the metabolism of rebamipide in human liver microsomes was compatible with that in a human cDNA-expressed CYP3A4 system, but not for other human P450 expression systems. It is therefore suggested that the hydroxylation of rebamipide only involves CYP3A4. 4. Rebampide showed no inhibitory effect on CYP1A2-, 2C9-, 2C19-, 2D6-, 2E1- and 3A4-catalysed metabolism. In addition, the metabolic contribution by CYP3A4 was considered to be slight for the overall elimination of rebamipide in man. It is therefore considered that drug interactions with cytochrome P450 enzymes are not involved in either the metabolism of rebamipide or the metabolism of other drugs concomitantly administered with rebamipide.     

Identification of human p450 isoforms involved in the metabolism of the antiallergic drug, oxatomide, and its inhibitory effect on enzyme activity

Oxatomide is an antiallergic drug used for the treatment of diseases mediated by type I allergy. Recently, it has been reported that terfenadine and astemizole, which have antiallergic actions similar to those of oxatomide, show side effects on the cardiovascular system, such as QT prolongation, ventricular arrhythmia and cardiac arrest. This might be because concomitant drugs such as itraconazole inhibit cytochrome P450 3A4 (CYP3A4), the enzyme responsible for degradation of terfenadine and astemizole, and thus the blood concentrations of the drugs are abnormally increased. On the other hand, isoforms of P450 involved in the metabolism of oxatomide have not been clarified. Therefore, we attempted to identify these isoforms using microsome preparations of in vitro expression systems derived from a human lymphoblastoid cell line. Oxatomide was metabolized by CYP2D6-Val and CYP3A4, but not by CYP1A2, CYP2C9-Arg, CYP2C9-Cys or CYP2C19. We also examined whether oxatomide showed inhibitory effects on metabolic activity of individual P450 isozymes using model substrates for each isozyme. Oxatomide did not inhibit the metabolism of the model substrates for CYP1A2, CYP2C9-Arg, CYP2C9-Cys and CYP2C19, but inhibited the degradation of those for CYP2D6-Val and CYP3A4. It was found that oxatomide is metabolized by CYP2D6 and CYP3A4 in human liver microsomes, and simultaneously acts as an inhibitor for these isoforms, responsible for the metabolism of the drug itself.     

Identification of the rat liver cytochrome P450 enzymes involved in the metabolism of the calcium channel blocker dipfluzine hydrochloride

This study aimed to identify the specific cytochrome P450 (CYP450) enzymes involved in the metabolism of dipfluzine hydrochloride using the combination of a chemical inhibition study, a correlation analysis and a panel of recombinant rat CYP450 enzymes. The incubation of Dip with rat liver microsomes yielded four metabolites, which were identified by liquid chromatography-coupled tandem mass spectrometry (LC/MS/MS). The results from the assays involving eight selective inhibitors indicated that CYP3A and CYP2A1 contributed most to the metabolism of Dip, followed by CYP2C11, CYP2E1 and CYP1A2; however, CYP2B1, CYP2C6 and CYP2D1 did not contribute to the formation of the metabolites. The results of the correlation analysis and the assays involving the recombinant CYP450 enzymes further confirmed the above results and concluded that CYP3A2 contributed more than CYP3A1. The results will be valuable in understanding drug–drug interactions when Dip is coadministered with other drugs.