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师少军 《中国医院药学杂志》2020,40(5):579-585
肝脏是药物代谢和排泄的主要器官。肝脏药物代谢酶和膜转运体对肝细胞内药物处置及其临床疗效和毒性产生重要影响。近年来,国内外学者发现被称为"代谢-转运互作"的动力学现象,其对药物药代动力学(生物利用度)、药物相互作用具有显著影响。药物代谢酶与转运体间的功能相互作用是目前药物代谢和药代动力学研究的热点之一。本文对肝脏代谢-转运互作进行了探究,并系统阐述了这种互作对药物(特别是Ⅱ相药物代谢)的药物相互作用、药代动力学、临床疗效和毒性反应的影响。今后应进一步阐明肝脏代谢-转运互作机制,有助于研究体内药物处置及药物相互作用,为临床合理用药提供新思路和新技术。 相似文献
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质子泵抑制剂对药物代谢酶CYP1A2、NAT2的影响分析 总被引:1,自引:0,他引:1
蔡连华 《中国现代药物应用》2007,1(10):33-34
目的 以健康人群作为研究对象,从代谢表型探讨质子泵抑制剂与药物代谢酶CYP1A2、NAT2的关系.方法 以咖啡因作为药物代谢酶CYP1A2、NAT2的探针药物,用反相高效液相色谱(RP-HPLC)方法测定尿液中咖啡因代谢物.结果 健康人群CYP1A2酶活性指标呈对数正态分布,NAT2酶活性活性指标呈两态分布.结论 以咖啡因探针法测定正常人肝脏药物代谢酶CYP1A2、NAT2活性的RP-HPLC梯度洗脱直接进样法,为国内深入开展CYP1A2、NAT2代谢酶的研究开拓了一种新方法. 相似文献
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了解药物交互作用的最好方法是研究其发生的机制与部位。药物相交作用可分为三大类: 一、药物代谢动力学交互作用:一种药物使同时服用的另一种药物的代谢动力学图象发生改变; 二、药效学交互作用:两药交互作用,引起药理作用的相加、增强或拮抗; 相似文献
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肝外药物代谢酶的研究进展 总被引:2,自引:0,他引:2
药物、毒物在肝外的代谢是其在体内代谢的重要组成部分,涉及到药效学、药代动力学、药物副作用、药物间相互作用和毒理学等方西,这个过程与肝外药物代谢酶密切相关。肝外药物代谢酶大多在肝内也有分布,与肝内药物代谢酶有相似之处,但又有其自身的特点。目前,肝外药物代谢酶的研究日益得到重视,本文就肝外药物代谢酶的种类、分布、主要作用、影响因素和研究方法等作一综述。 相似文献
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药物代谢分型的研究进展 总被引:5,自引:0,他引:5
目的:为了促进药物代谢分型研究在临床上的深放。方法:综述近几年具遗传多态性代谢酶的探针药物、代谢分型方法以及影响因素。介绍“Cooktail”分型法。比较代谢分型与基因分型两种分型方法。结果:疾病、并用药物、探药剂量、样本处理方法、服药依从性是代谢分型的主要影响因素。结论:药物代谢分型能指导临床安全合理有效地用药。基因分型与代谢分型各有优点,应灵活应用。“Cooktail”分型方法具有独特的优越性和发展前景,应大力开展在特殊群体中的代谢分型研究。 相似文献
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《药学学报(英文版)》2017,7(2):241-248
Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21st International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2–6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME) and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research. 相似文献
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Proxicromil was extensively metabolized and eliminated as metabolites in urine and faeces by the rat, hamster, rabbit, squirrel monkey, cynomolgus monkey, baboon and man after oral administration. The pathway of metabolism in these species was by hydroxylation of the alicyclic ring principally to yield monohydroxylated metabolites with trace amounts of a dihydroxylated product. Elimination of proxicromil by the dog, however, was essentially as the unchanged drug. The lack of metabolism of the drug by the dog resulted in the dog having a dependence on biliary excretion of the unchanged drug for clearance. These differences in clearance routes between species were reflected in the plasma clearance of the drug. The value for rat, a species capable of metabolism, was approximately 20 fold (4.1 ml min-1 kg-1) greater than the corresponding value for dog (0.2 ml min-1 kg-1). Inhibiting the metabolism of proxicromil in the rat with SKF-525A lowered plasma clearance of proxicromil (0.6 ml min-1 kg-1) and elevated the proportion of unchanged drug cleared by biliary excretion. 相似文献
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《药学学报(英文版)》2020,10(1):105-112
Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters. Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability (pharmacokinetics, or PK) and therapeutic efficacy (pharmacodynamics, or PD) of drugs. Recent studies have suggested that the long non-coding RNAs (lncRNAs) are highly relevant to drug metabolism and drug resistance, including chemo-resistance in cancers, through the regulation of drug metabolism and disposition related genes. This review summarizes the regulation of enzymes, transporters, or regulatory proteins involved in drug metabolism by lncRNAs, with a particular emphasis on drug metabolism and chemo-resistance in cancer patients. The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related lncRNAs are also proposed. Understanding the role of lncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms, but also enable the discovery of lncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients, including cancer patients. 相似文献
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《Drug metabolism reviews》2012,44(4):699-721
Human cytochrome P450 (CYP) 3A subfamily members (mainly CYP3A4 and CYP3A5) mediate the metabolism of approximately half all marketed drugs and thus play a critical role in the drug metabolism. A huge number of studies on CYP3A-mediated drug metabolism in humans have demonstrated that CYP3A activity exhibits marked ethnic and individual variability, in part because of altered levels of CYP3A4 expression by various environmental factors and functionally important polymorphisms present in CYP3A5 gene. Accumulating evidence has revealed that CYP3A4 and CYP3A5 have a significant overlapping in their substrate specificity, inducers and inhibitors. Therefore, it is difficult to define their respective contribution to drug metabolism and drug-drug interactions. Furthermore, P-glycoprotein and CYP3A are frequently co-expressed in the same cells and share a large number of substrates and modulators. The disposition of such drugs is thus affected by both metabolism and transport. In this review, we systematically summarized the frequently used CYP3A probe drugs, inducers and inhibitors, and evaluated their current status in drug development and research. 相似文献
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Drugs as CYP3A probes, inducers, and inhibitors 总被引:4,自引:0,他引:4
Human cytochrome P450 (CYP) 3A subfamily members (mainly CYP3A4 and CYP3A5) mediate the metabolism of approximately half all marketed drugs and thus play a critical role in the drug metabolism. A huge number of studies on CYP3A-mediated drug metabolism in humans have demonstrated that CYP3A activity exhibits marked ethnic and individual variability, in part because of altered levels of CYP3A4 expression by various environmental factors and functionally important polymorphisms present in CYP3A5 gene. Accumulating evidence has revealed that CYP3A4 and CYP3A5 have a significant overlapping in their substrate specificity, inducers and inhibitors. Therefore, it is difficult to define their respective contribution to drug metabolism and drug-drug interactions. Furthermore, P-glycoprotein and CYP3A are frequently co-expressed in the same cells and share a large number of substrates and modulators. The disposition of such drugs is thus affected by both metabolism and transport. In this review, we systematically summarized the frequently used CYP3A probe drugs, inducers and inhibitors, and evaluated their current status in drug development and research. 相似文献
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S Tanayama T Kobayashi Y Kanai 《Xenobiotica; the fate of foreign compounds in biological systems》1978,8(6):377-382
1. Accumulation and possible induction in the metabolism of triethoxybenzoylpropionate were studied in rats in relation to the choleretic effect of the drug. Daily oral administration of [14 C] triethoxybenzoylpropionate showed no accumulation of drug or metabolites. Pre-treatment of rats with the drug did not induce its own metabolism or the metabolism of aminopyrine, p-nitroanisole, hexobarbital or zoxazolamine. 2. Choleresis in rats induced by triethoxybenzoylpropionate resulted from enhanced formation of the bile acid-independent fraction of canalicular origin, presumably mediated by the increased transfer of sodium into the canaliculi. This was not altered by repeated pre-treatment with the drug, in accordance with the metabolic findings. 相似文献
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Hu G Siu SO Li S Chu IK Kwan YW Chan SW Leung GP Yan R Lee SM 《Xenobiotica; the fate of foreign compounds in biological systems》2012,42(3):294-303
Although zebrafish has become a popular animal model for drug discovery and screening, drug metabolism in zebrafish remains largely unknown. In this study, we probed the metabolic capability of zebrafish larvae with calycosin, one of the major isoflavone constituents of Radix Astragali that was previously demonstrated to be angiogenic in the zebrafish model. The metabolism of calycosin and accumulation of its metabolites in zebrafish larvae were determined using an LC-MS/MS method. Calycosin showed a slow but steady decrease from the culture medium as well as a steady accumulation in zebrafish larvae. Calycosin underwent major conjugation and minor oxidation in zebrafish larvae. A total of ten calycosin metabolites formed from glucuronidation, glucosylation, sulfation, oxidation or a combination of two of these metabolisms were identified, most of which were reported for the first time. Most metabolites increased steadily in the larvae over 24-h experimental period. The dominant phase II conjugation of calycosin in zebrafish larvae matched well with existing knowledge of isoflavone metabolism in mammalians. The findings shed a light in certain degree of similarity of phase II drug metabolism between zebrafish larvae and mammals and warrant further investigation on feasibility of adopting the zebrafish larvae as a whole-organism model for examining drug metabolism. 相似文献
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Svante Vikingsson Ariane Wohlfarth Mikael Andersson Henrik Gréen Markus Roman Martin Josefsson Fredrik C Kugelberg Robert Kronstrand 《The AAPS journal》2017,19(3):736-742
Meclonazepam is a benzodiazepine patented in 1977 to treat parasitic worms, which recently appeared as a designer benzodiazepine and drug of abuse. The aim of this study was to identify metabolites suitable as biomarkers of drug intake in urine using high-resolution mass spectrometry, authentic urine samples, and different model systems including human liver microsomes, cryopreserved hepatocytes, and a mice model. The main metabolites of meclonazepam found in human urine were amino-meclonazepam and acetamido-meclonazepam; also, minor peaks for meclonazepam were observed in three of four urine samples. These observations are consistent with meclonazepam having a metabolism similar to that of other nitro containing benzodiazepines such as clonazepam, flunitrazepam, and nitrazepam. Both metabolites were produced by the hepatocytes and in the mice model, but the human liver microsomes were only capable of producing minor amounts of the amino metabolite. However, under nitrogen, the amount of amino-meclonazepam produced increased 140 times. This study comprehensively elucidated meclonazepam metabolism and also illustrates that careful selection of in vitro model systems for drug metabolism is needed, always taking into account the expected metabolism of the tested drug. 相似文献
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Because of the propensity of nascently formed metabolites towards sequential metabolism within formation organs, theoretical and experimental treatments that achieve mass conservation must recognize the various sources contributing to primary, secondary, and tertiary metabolite formation. A simple one-compartment open model, with first-order conditions and the liver as the only organ of drug disappearance and metabolite formation, was used to illustrate the metabolism of a drug to its primary, secondary, and tertiary metabolites, encompassing the cascading effects of sequential metabolism. The concentration-time profiles of the drug and metabolites were examined for two routes of drug administration, oral and intravenous. Formation of the primary metabolite from drug in the gut lumen, with or without further absorption, and metabolite formation arising from first-pass metabolism of the drug and the primary metabolite during oral absorption were considered. Mass balance equations, incorporating modifications of the various absorption and conversion rate constants, were integrated to provide the explicit solutions. Simulations, with and without consideration of the sources of metabolite formation other than from its immediate precursor, were used to illustrate the expected differences in circulating metabolite concentrations. However, a simple relationship between the area under the curve of any metabolite, M, or [AUC (m)], its clearance [CL(m)], and route of drug administration was found. The drug dose, route, fraction absorbed into the portal circulation, Fabs, fraction available of drug from the liver, F, availabilities of the metabolites F(m) from formation organs, and CL(m) are determinants of the AUC(m)'s. After iv drug dosing, the area of any intermediary metabolites is determined by the iv drug dose divided by the (CL(m)/F(m] of that metabolite. When a terminal metabolite is not metabolized, its area under the curve becomes the iv dose of drug divided by the clearance of the terminal metabolite since the available fraction for this metabolite is unity. Similarly, after oral drug administration, when loss of drug in the gut lumen does not contribute to the appearance of metabolites systematically, the general solution for AUC(m) is the product of Fabs and oral drug dose divided by [CL(m)/F(m)]. A comparison of the area ratios of any metabolite after po and iv drug dosing, therefore, furnishes Fabs. When this fraction is divided into the overall systemic availability or Fsys, the drug availability from the first-pass organs, F, may be found.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
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Alfaro CL 《Psychopharmacology bulletin》2001,35(4):80-93
Significant scientific advancements in the last decade have armed researchers with tools to assess drug metabolism and the effects of drugs on metabolic pathways; however, most of this research has focused on cytochrome P450 isozymes. Early delineation of this information aids in the prediction of potential drug-drug interactions, which may ultimately determine whether a compound is pursued in the drug development process. The recent withdrawals of medications such as terfenadine, astemizole, cisapride, and mibefradil from the market demonstrate the relevance of this a priori approach--the risk of drug interactions was largely unrecognized prior to their approval by the Food and Drug Administration (FDA). Drug interaction studies for new drug applications (NDAs) field between 1987 and 1991 were largely in vivo studies with potential coadministered drugs, whereas for NDAs field between 1992 and 1997, the majority of studies involved metabolic mechanisms and in vitro methodology. Despite current limitations in the extrapolation of in vitro drug metabolism data to the in vivo environment, in vitro studies remain the mainstay of initial evaluations in this area primarily because of the high throughput nature of these investigations and the reduced cost compared with in vivo studies. The FDA has published several guidance documents in the area of drug metabolism and drug interaction studies in drug development with suggestions for in vitro as well as in vivo approaches to these investigations. Current and future research will likely focus on in vitro models for cytochrome P450 induction, Phase II metabolism, and drug transporters, and include validation and extrapolation of these approaches in vivo. 相似文献