硫唑嘌呤代谢酶基因多态性与其导致的不良反应的相关性研究进展

硫唑嘌呤代谢过程中涉及众多的代谢酶,这些代谢酶基因的多态性与硫唑嘌呤的药物不良反应密切相关。充分认识硫唑嘌呤代谢相关的酶的基因多态性在硫唑嘌呤药物体内代谢过程中的作用及其遗传多态性与药物不良反应的关系,并在用药治疗之前,对患者进行代谢酶的基因型分析,可以帮助临床医师更加安全和个体化的给患者提供治疗用药。     

心血管药物代谢酶及其遗传药理学研究进展

目的:为心血管药物的临床合理应用和个体化给药提供参考。方法:检索近年来国内、外遗传药理学和药物基因组学在心血管药物代谢酶研究方面的论文,对其进行分析、归纳和总结。结果与结论:药物代谢酶的基因多态性是心血管药物疗效和不良反应产生个体差异的重要原因,是个体化给药的依据。     

瑞苏伐他汀遗传药理学研究进展

胆固醇水平升高是动脉粥样硬化发病的主要原因。瑞苏伐他汀为临床常用的抑制胆固醇合成的药物,其药动学和药效学存在显著个体差异。药物转运体、药物代谢酶、药物靶点的遗传多态性对瑞苏伐他汀的体内代谢和临床疗效个体差异具有重要作用。本文阐述了药物转运体、细胞色素P450酶和其他相关基因的遗传多态性对瑞苏伐他汀药动学和药效学的影响,为临床制定个体化用药方案提供参考。     

药物代谢酶细胞色素P450 2D6的遗传多态性研究进展

CYP2D6是肝脏中重要的药物代谢酶,其代谢的药物占临床应用药物的20%～25%.其遗传多态性对依赖CYP2D6代谢的药物具有重要的影响.本文综述了CYP2D6在遗传多态性方面的研究进展及其临床意义.     

细胞色素P450基因多态性对心血管药物疗效的影响

基因多态性对药物疗效的影响主要表现在药物代谢酶的多态性、药物受体的多态性和药物靶标的多态性,其中药物代谢酶的基因多态性是导致相同药物、相同剂量、不同个体差异的一个重要生物学因素。遗传药理学（pharmacogenetics）即是从基因水平揭示个体的遗传特质对酶活性、受体蛋白和药物靶标的影响,从基因水平阐释药物效应差异的原因,以及各种基因表型与药物疗效、毒副反应之间的关系。     

药物作用的遗传差异

目的:临床上药物遗传对药物的个体差异起着十分重要的作用.方法:查阅近几年文献.结果:药物Ⅰ相和Ⅱ相代谢中不乏存在遗传引起药物个体差异的现象,如细胞色素P450酶的遗传多态性使同样药物、同样剂量的治疗对不同个体产生不同药物反应,因而了解其机理并开发出临床上可行的检测方法有利于临床实行个体化治疗.结论:随着人类基因组工程的进展,遗传基因编码的药物代谢酶、转运蛋白、药物受体等会逐步了解,使临床医生对每个患者能选择更为合适的药物、更为合适的剂量治疗疾病.     

CYP2D6基因多态性及对药物代谢的影响

CYP2D6代谢酶是细胞色素P450家族中的成员之一,是参与Ⅰ相代谢和众多内源性物质和不同药物消除的酶。虽然它在肝脏中的含量大约只占肝脏总量的2%,但在临床上却参与了25%以上的常用药物的代谢活动。在所有参与药物代谢的细胞色素P450基因家族中,CYP2D6是唯一不能被诱导的酶,这种酶具有广泛的多态性,这种多态性对酶的药物代谢功能具有重要影响,CYP2D6的这种多态性和药物代谢功能所表现的对个体活性的差异,在遗传药理学上具有重要意义。本文从CYP2D6基因多态性和它对药物代谢的影响这两方面进行了阐述。     

肿瘤化疗与药物代谢酶遗传多态性的关系

遗传药理学(Pharrnacogenetics)是研究机体遗传变异引起的药物反应异常的一门新兴学科。遗传药理学研究表明，遗传是药物在人体内的处置与机体对之产生反应的决定因素，是产生药物代谢与反应个体差异的重要原因。具体表现为药物代谢酶和(或)受体表达的改变，而药物代谢酶的多态性似乎比受体多态性更常见。     

肿瘤化疗与药物代谢酶遗传多态性的关系

遗传药理学(Pharmacogenetics)是研究机体遗传变异引起的药物反应异常的一门新兴学科.遗传药理学研究表明,遗传是药物在人体内的处置与机体对之产生反应的决定因素,是产生药物代谢与反应个体差异的重要原因[1].具体表现为药物代谢酶和(或)受体表达的改变,而药物代谢酶的多态性似乎比受体多态性更常见[2].……     

药物代谢酶遗传多态性对药物神经毒性的影响

神经毒性是药物常见的毒性反应之一。神经系统对药物引起的损害尤其敏感,药物引起神经系统结构和功能的微小改变即可表现出严重的精神或行为异常,因此药物引起的神经毒性越来越得到人们的关注。药物引起的神经毒性存在个体差异,其中遗传因素对这种差异的产生发挥重要作用。药物代谢酶影响药物体内的生物转化过程,因此代谢酶的遗传多态性在一定程度上决定了不同个体对药物神经毒性的易感性。本篇综述将着重探讨药物代谢酶中的细胞色素P450酶、谷胱甘肽转移酶和N-乙酰转移酶遗传多态性对药物神经毒性易感性的影响。     

转运体介导的食物-药物相互作用

食物与药物之间的相互作用普遍存在,且作用机制也多种多样。目前,研究较多的是单个食物或食物中的某些营养成分通过调节药物转运体或代谢酶的功能从而影响药物的体内过程。食物对药物体内过程的影响包括吸收、分布、代谢、排泄四个方面,并且主要是调节其中参与的药物转运体和代谢酶的功能。转运体介导的食物对药物体内吸收的影响主要是通过调节肠上皮摄取型和外排型的转运体,从而影响药物的吸收;对分布的影响主要是通过调节体内一些屏障中的转运体;对代谢的影响主要是同时调节药物代谢酶和转运体;对排泄的影响是通过调节肾脏和肝脏胆汁排泄的药物转运体,从而影响药物的清除率。因此,转运体介导的食物与药物相互作用直接影响药物治疗的效果。     

Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and children

INTRODUCTION: There are profound changes that take place in drug metabolism enzymes during fetal and postnatal development. These changes may significantly impact drug therapy in children. AREAS COVERED: A combination of focused and comprehensive literature searches using PubMed and reference lists (from inception to 7 November 2009) is undertaken to identify reports on in vitro and in vivo development of drug metabolism enzymes as well disposition of selected drugs and their effect in children. The article provides an update on development of drug metabolism enzymes and their impact on drug substrate disposition and disease, which may aid to improve clinical practice and optimally design clinical trials in children. EXPERT OPINION: Drug metabolism enzyme activity changes profoundly throughout the continuum of postnatal development and often results in different disposition pathways than in adults. Genetics and co-morbidity interact significantly with these developmental changes. Translation of existing knowledge into age-adjusted dosing guidelines and clinical trial design is highly needed for there to be an improvement in drug therapy in children.     

慢性肾脏病对药物转运和代谢的影响

本文介绍了慢性肾脏病状态下,肾脏、肝脏及肠道中主要代谢酶和药物转运体介导药物转运和代谢的最新研究进展,以期为临床合理用药提供参考。肾脏疾病对肾脏、肝脏和肠道转运体及代谢酶均有一定的影响,是与肾脏本身器质性病变协同进展而表现出来的病理生理过程。在科研及临床实践中,有必要将肾脏疾病对其他器官的影响一并分析、综合考虑,以作出最客观最合理的判断。     

Problems and perspectives of phenotyping for drug-metabolizing enzymes in man

Pronounced interindividual differences in drug disposition are mainly caused by differences in the activity of liver drug-metabolizing enzymes. These depend on known and unknown covariates, including genetic as well as environmental factors. Phenotyping, i.e. assessment of enzyme activities in vivo after administration of a test dose, seems to be a promising tool for determining actual metabolic capacities. Although it is a well-established experimental approach, phenotyping has not yet found its way into clinical practice. Main reasons for this are lack of validation for many probes and assays used, complicated procedures, invasiveness, semi-quantitative test results, non-compliance on behalf of the subjects tested, high costs, and lack of prospective clinical studies to assess the benefit of phenotyping for patients. Problems and perspectives of phenotyping are exemplified for the cytochrome P-450 enzymes CYP1A2 and CYP3A4, two major human drug-metabolizing enzymes.     

HMG-CoA reductase inhibitors: assessing differences in drug interactions and safety profiles

OBJECTIVE: To review the cytochrome P450 system and associated metabolic differences between the HMG-CoA reductase inhibitors. DATA SOURCES: A MEDLINE search (1993-99) was conducted for English-language articles using key search terms including adverse drug reactions, cytochrome P450, drug metabolism, drug interactions, hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, myopathy, and rhabdomyolysis. STUDY SELECTION: Review articles, clinical trials, and case reports concerning HMG-CoA reductase inhibitor metabolism, drug interactions, and adverse drug reactions were evaluated. DATA EXTRACTION: By the author. No software or assistants were used to extract information from the chosen studies. DATA SYNTHESIS: The cytochrome P450 enzymes, which can be divided into families, subfamilies, and isoenzymes, act as a major catalyst for drug oxidation in the liver. CYP3A4 is a major enzyme, accounting for about 60% of drug metabolic capacity in the liver and 70% of such function in the intestine. Lovastatin, simvastatin, and atorvastatin are substrates of CYP3A4, whereas fluvastatin is metabolized by CYP2C9. Pravastatin is not extensively metabolized by either of these isoenzymes; rather, it is transported into hepatocytes by a sodium-independent, carrier-mediated uptake system that normally transports bile acids. Compared with other statins, pravastatin thus has a reduced potential for drug interactions with other substrates, inhibitors, or inducers of the CYP3A4 and CYP2C9 systems. CONCLUSION: Pharmacists must understand the functions of these enzymes to identify potential drug interactions, especially in high-risk patient populations, and to make appropriate therapeutic recommendations that prevent or minimize adverse clinical outcomes.     

Metabolic complications associated with HIV protease inhibitor therapy

HIV protease inhibitors were introduced into clinical practice over 7 years ago as an important component of combination antiretroviral drug regimens which in many ways revolutionised the treatment of HIV infection. The significant improvements in prognosis that have resulted from the use of these regimens, combined with the need for lifelong treatment, have increasingly focused attention on the adverse effects of antiretroviral drugs and on the metabolic complications of HIV protease inhibitors in particular. In this review, the cluster of metabolic abnormalities characterised by triglyceride-rich dyslipidaemia and insulin resistance associated with HIV protease inhibitor therapy are considered, along with implications for cardiovascular risk in patients affected by these complications. Toxicity profiles of individual drugs within the HIV protease inhibitor class are examined, as there is an increased recognition of significant intra-class differences both in terms of absolute risk of metabolic complications as well as the particular metabolic phenotype associated with these drugs. Guidelines for clinical assessment and treatment are emphasised, along with pathophysiological mechanisms that may provide a rational basis for the treatment of metabolic complications. Finally, these drug-specific effects are considered within the context of HIV-specific effects on lipid metabolism as well as lifestyle factors that have contributed to a rapidly increasing incidence of similar metabolic syndromes in the general population. These data highlight the importance of individualising patient management in terms of choice of antiretroviral regimen, assessment of metabolic outcomes and use of therapeutic interventions, based on the assessment of baseline (pre-treatment) metabolic status as well as the presence of potentially modifiable cardiovascular risk factors.