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Drug Metabolism Reviews Feb 2021Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a... (Review)
Review
Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a variety of xenobiotic get overexpressed in malignant cells, therefore, catalyzing drug inactivation. As evident from the literature reports, the levels of DMEs increase in cancer cells that ultimately lead to drug inactivation followed by drug resistance. To puzzle out this issue, several strategies inclusive of analog designing, prodrug designing, and inhibitor designing have been forged. On that front, the implementation of computational tools can be considered a fascinating approach to address the problem of chemoresistance. Various research groups have adopted different molecular modeling tools for the investigation of DMEs mediated toxicity problems. However, the utilization of these tools in maneuvering the DME mediated chemoresistance is least considered and yet to be explored. These tools can be employed in the designing of such chemotherapeutic agents that are devoid of the resistance problem. The current review canvasses various molecular modeling approaches that can be implemented to address this issue. Special focus was laid on the development of specific inhibitors of DMEs. Additionally, the strategies to bypass the DMEs mediated drug metabolism were also contemplated in this report that includes analogs and pro-drugs designing. Different strategies discussed in the review will be beneficial in designing novel chemotherapeutic agents that depreciate the resistance problem.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Xenobiotics
PubMed: 33535824
DOI: 10.1080/03602532.2021.1874406 -
The Pharmacogenomics Journal Feb 2013Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II... (Meta-Analysis)
Meta-Analysis Review
Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II drug-metabolizing enzymes (DMEs) are polymorphic and constitute essential factors for the outcome of drug therapy. Recently, both genome-wide association (GWA) studies with a focus on drug response, as well as more targeted studies of genes encoding DMEs have revealed in-depth information and provided additional information for variation in drug metabolism and drug response, resulting in increased knowledge that aids drug development and clinical practice. In addition, an increasing number of meta-analyses have been published based on several original and often conflicting pharmacogenetic studies. Here, we review data regarding the pharmacogenomics of DMEs, with particular emphasis on novelties. We conclude that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP2C9 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1. Furthermore, the analgesic and side effects of codeine in relation to CYP2D6 polymorphism are supported and the influence of CYP2D6 genotype on breast cancer recurrence during tamoxifen treatment appears relevant as based on three large studies. The influence of CYP2D6 polymorphism on the effect of antidepressants in a clinical setting is yet without any firm evidence, and the relation between CYP2D6 ultrarapid metabolizers and suicide behavior warrants further studies. There is evidence for the influence of CYP3A5 polymorphism on tacrolimus dose, although the influence on response is less studied. Recent large GWA studies support a link between CYP1A2 polymorphism and blood pressure as well as coffee consumption, and between CYP2A6 polymorphism and cigarette consumption, which in turn appears to influence the lung cancer incidence. Regarding phase II enzyme polymorphism, the anticancer treatment with mercaptopurines and irinotecan is still considered important in relation to the polymorphism of TPMT and UGT1A1, respectively. There is a need for further clarification of the clinical importance and use of all these findings, but the recent research in the field that encompasses larger studies and a whole genome perspective, improves the possibilities be able to make firm and cost-effective recommendations for drug treatment in the future.
Topics: Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic
PubMed: 23089672
DOI: 10.1038/tpj.2012.45 -
Clinical Biochemistry Apr 1986Biotransformation of drugs to polar metabolites is a key step in the termination of action and the elimination of drugs used in therapeutics. A large number of factors,... (Review)
Review
Biotransformation of drugs to polar metabolites is a key step in the termination of action and the elimination of drugs used in therapeutics. A large number of factors, including infection, alter the basal rates of drug metabolism and cause a number of untoward effects and drug interactions. Although a number of techniques have been attempted, there appears to be no easy way to determine the capacity of an individual to metabolize a specific drug and to tailor drug dosage to that individual.
Topics: Biotransformation; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Infections; Kinetics; Liver; Metabolic Clearance Rate; Pharmaceutical Preparations
PubMed: 3518991
DOI: 10.1016/s0009-9120(86)80051-0 -
Pharmacology & Therapeutics 1993Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome... (Review)
Review
Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
Topics: Animals; Humans; Metabolism; Polymorphism, Genetic
PubMed: 8361990
DOI: 10.1016/0163-7258(93)90053-g -
Critical Reviews in Food Science and... Jul 2016Isoflavones are the most widely consumed phytoestrogens. Besides being a dietary constituent, their consumption has been increasing in the form of herbal supplements and... (Review)
Review
Isoflavones are the most widely consumed phytoestrogens. Besides being a dietary constituent, their consumption has been increasing in the form of herbal supplements and as promising alternatives to hormonal replacement therapy, in conjunction with prescription medicines. Isoflavones are extensively metabolized by phase I and II enzymes and are substrates of drug transporters. At high concentrations isoflavones may interact with drug metabolizing enzymes and drug transporters and modulate their activity, thus, altering the absorption, metabolism, distribution, excretion and toxicity profile of the co-administered drugs. This review summarizes the up-to-date literature of isoflavone-drug interactions giving insight into the possible mechanisms of interactions, in vitro-in vivo correlation and their implications on clinical outcomes.
Topics: Animals; Cytochrome P-450 Enzyme System; Disease Models, Animal; Herb-Drug Interactions; Humans; Inactivation, Metabolic; Isoflavones; Phytoestrogens; Phytotherapy; Plants, Medicinal; Prescription Drugs
PubMed: 26561312
DOI: 10.1080/10408398.2015.1045968 -
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 -
Science (New York, N.Y.) Apr 1959A number of drugs that are metabolized through the action of enzymes present in liver microsomes in the adult rabbit are not metabolized in livers of newborn rabbits....
A number of drugs that are metabolized through the action of enzymes present in liver microsomes in the adult rabbit are not metabolized in livers of newborn rabbits. The development of metabolic pathways during a period of 4 weeks is presented. Evidence is given for the presence in livers of baby rabbits of inhibitors of some of these drug-enzyme systems.
Topics: Animals; Liver; Metabolic Networks and Pathways; Microsomes, Liver; Pharmaceutical Preparations; Rabbits
PubMed: 13635031
DOI: 10.1126/science.129.3353.897 -
British Journal of Clinical Pharmacology Mar 2008What is already known about this subject. The activity of drug-metabolizing enzymes, primarily cytochrome P450 enzymes, can determine a patient's response to a drug.... (Comparative Study)
Comparative Study
UNLABELLED
What is already known about this subject. The activity of drug-metabolizing enzymes, primarily cytochrome P450 enzymes, can determine a patient's response to a drug. Therapeutic failure or drug toxicity in the postoperative period after liver transplantation is influenced by the drug metabolizing capacity of the graft. Dose adjustment or selection of an alternative drug, which is not a substrate for the polymorphic enzyme may prevent the development of side-effects in recipients of poor metabolizer liver grafts. What this study adds. A validated analytical system with metabolomic tools has been developed to estimate the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates the improvement of individual recipient therapy. In the test of drug-metabolizing status, one of the liver grafts was found to be a CYP2C9 poor metabolizer, while the other was a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.
AIMS
The drug-metabolizing capacity of transplanted liver highly influences drug efficacy or toxicity, particularly in the early postoperative period. The aim of our study was to predict therapeutic failures or severe adverse drug reactions by phenotyping for cytochrome P450 (P450) polymorphism resulting in reduced or no activity of the key drug-metabolizing enzymes.
METHODS
A validated analytical system with metabolomic tools has been developed for estimation of the drug-metabolizing capacity of transplanted liver, which allows the prediction of potential poor metabolizer phenotypes of donors and facilitates improvement of the individual recipient therapy.
RESULTS
Of the 109 liver donors in Hungary, the frequency of poor metabolizers was found to be 0.92%, 5.5% and 8.3% for CYP2C9, CYP2C19 and CYP2D6, respectively. In the present study, two liver grafts transplanted in paediatric recipients were reported to be poor metabolizer phenotypes. The liver grafts presented normal function in the early postoperative days; 2 weeks after transplantation, however, increasing liver enzymes were detected. Histological investigation of a liver biopsy suggested drug toxicity. The test of drug metabolizing status showed one of the liver grafts to be a CYP2C9 poor metabolizer, and the other was found to be a CYP2C19 poor metabolizer. Rationalization of the medication resulted in the recovery of both the grafts and the recipients within 1 week.
CONCLUSIONS
Prospective investigation of the P450 status may lead to the optimization of drug choice and/or dose for a more effective therapy, avoid serious adverse effects, and decrease medical costs. Phenotyping donor livers and tailored medication can contribute to the improvement of graft and recipient survival.
Topics: Adolescent; Adult; Aged; Child; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Variation; Humans; Liver; Liver Transplantation; Male; Middle Aged; Pharmaceutical Preparations; Tissue Donors
PubMed: 18070218
DOI: 10.1111/j.1365-2125.2007.03056.x -
Current Drug Safety Nov 2012Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall... (Review)
Review
Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall cell mechanisms of drug metabolization, and more specifically drug processing are reviewed in normal EKs. The overall drug metabolism involves different phases corresponding to the uptake, biotransformation and anti-transport steps. In EKs, both the enzymes and transportassociated proteins are different from those involved in the hepatocyte metabolism. Some cytochrome P450 enzymes and the flavin-containing mono-oxygenases are particularly involved in EKs. Basically, EKs represent key cells likely involved during the initial stage of drug-induced toxic epidermal necrolysis (TEN). Only limited advances have been made so far in this field. Nevertheless, mitigating EKs metabolic disturbances in TEN probably represent a promising specific treatment of the disease.
Topics: Biotransformation; Drug Interactions; Humans; Keratinocytes; Pharmaceutical Preparations; Stevens-Johnson Syndrome
PubMed: 23373550
DOI: 10.2174/157488612805076507 -
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