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Yakugaku Zasshi : Journal of the... 2017Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug... (Review)
Review
Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed.
Topics: Binding Sites; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Inactivation, Metabolic; MicroRNAs; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic; Polymorphism, Single Nucleotide; RNA Editing; RNA Processing, Post-Transcriptional
PubMed: 28566576
DOI: 10.1248/yakushi.16-00250-5 -
International Journal of Molecular... Oct 2020In vitro methods which incorporate metabolic capability into the assays allow us to assess the activity of metabolites from their parent compounds. These methods can be... (Review)
Review
In vitro methods which incorporate metabolic capability into the assays allow us to assess the activity of metabolites from their parent compounds. These methods can be applied into high-throughput screening (HTS) platforms, thereby increasing the speed to identify compounds that become active via the metabolism process. HTS was originally used in the pharmaceutical industry and now is also used in academic settings to evaluate biological activity and/or toxicity of chemicals. Although most chemicals are metabolized in our body, many HTS assays lack the capability to determine compound activity via metabolism. To overcome this problem, several in vitro metabolic methods have been applied to an HTS format. In this review, we describe in vitro metabolism methods and their application in HTS assays, as well as discuss the future perspectives of HTS with metabolic activity. Each in vitro metabolism method has advantages and disadvantages. For instance, the S9 mix has a full set of liver metabolic enzymes, but it displays high cytotoxicity in cell-based assays. In vitro metabolism requires liver fractions or the use of other metabolically capable systems, including primary hepatocytes or recombinant enzymes. Several newly developed in vitro metabolic methods, including HepaRG cells, three-dimensional (3D) cell models, and organ-on-a-chip technology, will also be discussed. These newly developed in vitro metabolism approaches offer significant progress in dissecting biological processes, developing drugs, and making toxicology studies quicker and more efficient.
Topics: Cells, Cultured; Drug Evaluation, Preclinical; Hepatocytes; High-Throughput Screening Assays; Humans; Inactivation, Metabolic
PubMed: 33142951
DOI: 10.3390/ijms21218182 -
Neuroscience and Biobehavioral Reviews Sep 2014Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a... (Review)
Review
Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a drug. Current evidence demonstrates a gene-, stress- and species-specific interference in stress-mediated regulation of genes encoding the major drug-metabolizing CYP isozymes. Stress-induced up-regulation of CYPs that metabolize the majority of prescribed drugs can result in their increased metabolism and consequently, in failure of pharmacotherapy. In contrast, stress-induced down-regulation of CYP isozymes, including CYP2E1 and CYP2B1/2, potentially reduces metabolism of several toxicants and specific drugs-substrates resulting in increased levels and altered toxicity. The primary stress effectors, the adrenergic receptor-linked pathways and glucocorticoids, play primary and distinct roles in stress-mediated regulation of CYPs. Evidence demonstrates that stress regulates major drug metabolizing CYP isozymes, suggesting that stress should be considered to ensure pharmacotherapy efficacy and minimize drug toxicity. A detailed understanding of the molecular events underlying the stress-dependent regulation of drug metabolizing CYPs is crucial both for the design of new drugs and for physiology-based pharmacokinetic and pharmacodynamic modeling.
Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Pharmacokinetics; Stress, Psychological
PubMed: 24877684
DOI: 10.1016/j.neubiorev.2014.05.011 -
European Journal of Drug Metabolism and... Oct 2017Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents... (Review)
Review
Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone-artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens.
Topics: Animals; Antimalarials; Genetic Variation; Humans; Inactivation, Metabolic; Malaria; Membrane Transport Proteins; Pharmacogenetics
PubMed: 28070879
DOI: 10.1007/s13318-016-0399-1 -
Drug Metabolism and Disposition: the... Aug 2016The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and...
The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.
Topics: Activation, Metabolic; Animals; Cytochrome P-450 Enzyme System; Glucuronosyltransferase; Humans; Inactivation, Metabolic; Oxidation-Reduction; Oxidoreductases; Substrate Specificity; Sulfotransferases; Xenobiotics
PubMed: 27298339
DOI: 10.1124/dmd.116.071753 -
Advances in Cancer Research 2019Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox... (Review)
Review
Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of "immunometabolism." Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes.
Topics: Animals; Antineoplastic Agents; Cellular Reprogramming; Energy Metabolism; Glycolysis; Humans; Immune System; Immunotherapy; Metabolome; Neoplasms; Signal Transduction; T-Lymphocytes; Tumor Microenvironment
PubMed: 31202359
DOI: 10.1016/bs.acr.2019.03.004 -
Current Drug Metabolism 2022The characteristics of pharmacokinetics and the activity and expression of drugmetabolizing enzymes and transporters significantly change under a high-altitude hypoxic... (Review)
Review
BACKGROUND
The characteristics of pharmacokinetics and the activity and expression of drugmetabolizing enzymes and transporters significantly change under a high-altitude hypoxic environment. Gut microbiota is an important factor affecting the metabolism of drugs through direct or indirect effects, changing the bioavailability, biological activity, or toxicity of drugs and further affecting the efficacy and safety of drugs in vivo. A high-altitude hypoxic environment significantly changes the structure and diversity of gut microbiota, which may play a key role in drug metabolism under a high-altitude hypoxic environment.
METHODS
An investigation was carried out by reviewing published studies to determine the role of gut microbiota in the regulation of drug-metabolizing enzymes and transporters. Data and information on expression change in gut microbiota, drug-metabolizing enzymes, and transporters under a high-altitude hypoxic environment were explored and proposed.
RESULTS
High-altitude hypoxia is an important environmental factor that can adjust the structure of the gut microbiota and change the diversity of intestinal microbes. It was speculated that the gut microbiota could regulate drugmetabolizing enzymes through two potential mechanisms, the first being through direct regulation of the metabolism of drugs in vivo and the second being indirect, i.e., through the regulation of drug-metabolizing enzymes and transporters, thereby affecting the activity of drugs.
CONCLUSION
This article reviews the effects of high-altitude hypoxia on the gut microbiota and the effects of these changes on drug metabolism.
Topics: Altitude Sickness; Gastrointestinal Microbiome; Humans; Hypoxia; Inactivation, Metabolic; Membrane Transport Proteins
PubMed: 35088664
DOI: 10.2174/1389200223666220128141038 -
Nature Reviews. Drug Discovery Sep 2019Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely... (Review)
Review
Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of 'cellular selectivity based on demand', in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.
Topics: Autoimmune Diseases; Autoimmunity; Graft Rejection; Humans; Immune System; Immunomodulation; Inflammation; Metabolism; Models, Biological; Neoplasms
PubMed: 31363227
DOI: 10.1038/s41573-019-0032-5 -
Drug Metabolism Reviews May 2019Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide.... (Review)
Review
Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem.
Topics: Animals; Drug Resistance; Enzymes; Humans; Inactivation, Metabolic; Pharmaceutical Preparations; Pharmacology
PubMed: 31203662
DOI: 10.1080/03602532.2019.1632886 -
Current Drug Metabolism 2020Cancer is one of the most serious diseases threatening human health with high morbidity and mortality in the world. For the treatment of cancer, chemotherapy is one of... (Review)
Review
BACKGROUND
Cancer is one of the most serious diseases threatening human health with high morbidity and mortality in the world. For the treatment of cancer, chemotherapy is one of the most widely used strategies, for almost all kinds of tumors and diverse stages of tumor development. The efficacy of chemotherapy not only depends on the activity of the drug administrated but also on whether the compound could reach the effective therapeutic concentration in tumor cells. Therefore, expression and activity of drug-metabolizing enzymes (DMEs) in tumor tissues and metabolic organs of cancer patients are important for the dispositional behavior of anticancer drugs as well as the clinical response of chemotherapy.
METHODS
This review summarizes the recent advancement of the DMEs expression and activity in various cancers, as well as the potential regulatory mechanisms of major DMEs in cancer and cancer therapy.
RESULTS
Compared to normal tissues, expression and activity of major DMEs are significantly dysregulated in patients by various factors including epigenetic modification, ligand-activated transcriptional regulation and signaling pathways. Additionally, DMEs play an important role in anticancer drug efficacy, chemoresistance as well as the activation of prodrugs.
CONCLUSION
This review reinforces a more comprehensive understanding of DMEs in cancer and cancer therapy, and provides more opportunities for cancer therapy.
Topics: Animals; Antineoplastic Agents; Humans; Inactivation, Metabolic; Neoplasms; Signal Transduction; Transcription, Genetic
PubMed: 31902352
DOI: 10.2174/1389200221666200103111053