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Drug Metabolism Reviews Aug 2014Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design... (Review)
Review
Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines. The most common biotransformations include N-oxidation, N-conjugation, oxidative N-dealkylation, ring oxidation, and ring opening. In some instances, the metabolic pathways generate electrophilic reactive intermediates and cause bioactivation. However, potential bioactivation related adverse events can be attenuated by structural modifications. Hence it is important to understand the biotransformation pathways to design stable drug candidates that are devoid of metabolic liabilities early in the discovery stage. The current review provides a comprehensive summary of biotransformation and bioactivation pathways of aliphatic nitrogen containing heterocycles and strategies to mitigate metabolic liabilities.
Topics: Amines; Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Pharmaceutical Preparations
PubMed: 24909234
DOI: 10.3109/03602532.2014.924962 -
Cancer Research Sep 2015For decades, tumor cells have been considered defective in mitochondrial respiration due to their dominant glycolytic metabolism. However, a growing body of evidence is... (Review)
Review
For decades, tumor cells have been considered defective in mitochondrial respiration due to their dominant glycolytic metabolism. However, a growing body of evidence is now challenging this assumption, and also implying that tumors are metabolically less homogeneous than previously supposed. A small subpopulation of slow-cycling cells endowed with tumorigenic potential and multidrug resistance has been isolated from different tumors. Deep metabolic characterization of these tumorigenic cells revealed their dependency on mitochondrial respiration versus glycolysis, suggesting the existence of a common metabolic program active in slow-cycling cells across different tumors. These findings change our understanding of tumor metabolism and also highlight new vulnerabilities that can be exploited to eradicate cancer cells responsible for tumor relapse.
Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Cell Division; Citric Acid Cycle; DNA, Mitochondrial; Genes, Mitochondrial; Glucose; Glycolysis; Humans; Mitochondria; Models, Biological; Mutation; Neoplasms; Neoplastic Stem Cells; Oxidative Phosphorylation
PubMed: 26374463
DOI: 10.1158/0008-5472.CAN-15-0491 -
Advances in Pharmacology (San Diego,... 2022Numerous steps in drug development, including the generation of authentic metabolites and late-stage functionalization of candidates, necessitate the modification of... (Review)
Review
Numerous steps in drug development, including the generation of authentic metabolites and late-stage functionalization of candidates, necessitate the modification of often complex molecules, such as natural products. While it can be challenging to make the required regio- and stereoselective alterations to a molecule using purely chemical catalysis, enzymes can introduce changes to complex molecules with a high degree of stereo- and regioselectivity. Cytochrome P450 enzymes are biocatalysts of unequalled versatility, capable of regio- and stereoselective functionalization of unactivated CH bonds by monooxygenation. Collectively they catalyze over 60 different biotransformations on structurally and functionally diverse organic molecules, including natural products, drugs, steroids, organic acids and other lipophilic molecules. This catalytic versatility and substrate range makes them likely candidates for application as potential biocatalysts for industrial chemistry. However, several aspects of the P450 catalytic cycle and other characteristics have limited their implementation to date in industry, including: their lability at elevated temperature, in the presence of solvents, and over lengthy incubation times; the typically low efficiency with which they metabolize non-natural substrates; and their lack of specificity for a single metabolic pathway. Protein engineering by rational design or directed evolution provides a way to engineer P450s for industrial use. Here we review the progress made to date toward engineering the properties of P450s, especially eukaryotic forms, for industrial application, and including the recent expansion of their catalytic repertoire to include non-natural reactions.
Topics: Biocatalysis; Biological Products; Cytochrome P-450 Enzyme System; Drug Discovery; Humans; Substrate Specificity
PubMed: 35953156
DOI: 10.1016/bs.apha.2022.06.001 -
Scientific Reports Jan 2021Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet...
Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet the cellular and metabolic processes within the biological component of this system are still elusive. Here we dissect the biohybrid composed of the anaerobic acetogenic bacterium Moorella thermoacetica and cadmium sulphide nanoparticles (CdS) in terms of physiology, metabolism, enzymatics and transcriptomic profiling. Our analyses show that while the organism does not grow on L-cysteine, it is metabolized to acetate in the biohybrid system and this metabolism is independent of CdS or light. CdS cells have higher metabolic activity, despite an inhibitory effect of Cd on key enzymes, because of an intracellular storage compound linked to arginine metabolism. We identify different routes how cysteine and its oxidized form can be innately metabolized by the model acetogen and what intracellular mechanisms are triggered by cysteine, cadmium or blue light.
Topics: Acetates; Biological Transport; Cadmium; Carbon; Carbon Isotopes; Complex Mixtures; Cysteine; Energy Metabolism; Gene Expression Regulation, Bacterial; Light; Magnetic Resonance Spectroscopy; Moorella; Oxidation-Reduction; Transcriptome
PubMed: 33495538
DOI: 10.1038/s41598-021-81103-z -
Xenobiotica; the Fate of Foreign... Jan 2020The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of... (Review)
Review
The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism.Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 and reduce metabolism of drug substrates , in some cases increasing drug efficacy or toxicity.Common variants of have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations.Elevated plasma concentrations of trimethylamine -oxide, a product of an FMO3-catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine -oxide is a cause, effect or biomarker of the disease.Genetic variants of other s are also briefly discussed.
Topics: Adult; Humans; Inactivation, Metabolic; Metabolism, Inborn Errors; Methylamines; Oxygenases; Polymorphism, Genetic
PubMed: 31317802
DOI: 10.1080/00498254.2019.1643515 -
Drug Metabolism and Disposition: the... Aug 2015The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014...
The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic β-cell dysfunction and may have a role in how uremic toxins enter pancreatic β-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.
Topics: Animals; Biological Transport; Biological Transport, Active; Drug Delivery Systems; Humans; Inactivation, Metabolic; Pharmaceutical Preparations
PubMed: 25986849
DOI: 10.1124/dmd.115.064576 -
Frontiers in Pharmacology 2023Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an...
Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an integrated metabolomics, culturomics, and bionics framework for systematically studying probiotics-driven drug metabolism. We discovered that 75% (27/36 of the assayed drugs) were metabolized by five selected probiotics, and drugs containing nitro or azo groups were more readily metabolized. As proof-of-principle experiments, we showed that Zhang (LCZ) could metabolize racecadotril to its active products, S-acetylthiorphan and thiorphan, in monoculture, in a near-real simulated human digestion system, and in an fecal co-culture system. However, a personalized effect was observed in the racecadotril-metabolizing activity of Zhang, depending on the individual's host gut microbiome composition. Based on data generated by our workflow, we proposed a possible mechanism of interactions among Zhang, racecadotril, and host gut microbiome, providing practical guidance for probiotic-drug co-treatment and novel insights into precision probiotics.
PubMed: 36778014
DOI: 10.3389/fphar.2023.1047863 -
Physiology & Behavior Dec 2015Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic... (Review)
Review
Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic effects. However, data from several epidemiological studies have found that consumption of NNSs, mainly in diet sodas, is associated with increased risk to develop obesity, metabolic syndrome, and type 2 diabetes. The main purpose of this article is to review recent scientific evidence supporting potential mechanisms that explain how "metabolically inactive" NNSs, which have few, if any, calories, might promote metabolic dysregulation. Three potential mechanisms, which are not mutually exclusive, are presented: 1) NNSs interfere with learned responses that contribute to control glucose and energy homeostasis, 2) NNSs interfere with gut microbiota and induce glucose intolerance, and 3) NNSs interact with sweet-taste receptors expressed throughout the digestive system that play a role in glucose absorption and trigger insulin secretion. In addition, recent findings from our laboratory showing an association between individual taste sensitivity to detect sucralose and sucralose's acute effects on metabolic response to an oral glucose load are reported. Taken as a whole, data support the notion that NNSs have metabolic effects. More research is needed to elucidate the mechanisms by which NNSs may drive metabolic dysregulation and better understand potential effects of these commonly used food additives.
Topics: Animals; Energy Metabolism; Enteroendocrine Cells; Humans; Non-Nutritive Sweeteners
PubMed: 26095119
DOI: 10.1016/j.physbeh.2015.06.024 -
Yao Xue Xue Bao = Acta Pharmaceutica... Nov 2016UDP-glucuronosyltransferase (UGT), a kind of phase II drug-metabolizing enzyme, catalyzes the conjugation of glucuronic acid and drugs. UGTs are widely expressed in... (Review)
Review
UDP-glucuronosyltransferase (UGT), a kind of phase II drug-metabolizing enzyme, catalyzes the conjugation of glucuronic acid and drugs. UGTs are widely expressed in brain, but at a relatively low level compared to that in liver. Brain UGTs are inducible or inhibitable, which influences the drug distribution in the central nervous system. UGTs, cytochrome P450 (CYPs) and transporters act together to effect pharmacokinetics of drugs in brain. Several drugs have the capacity to cross the blood brain barrier after glucuronidation and certain drugs may be subject to direct glucuronidate in brain by the function of UGTs. The brain UGTs’ isoforms, localization, induction, inhibition, and interaction with CYP and transporters are introduced in this review. The process of drug glucuronidation and distribution in brain is summarized for five drugs. A deep insight into the process of drug metabolism and distribution in brain may provide a valuable reference for drug design for the central nervous system.
Topics: Blood-Brain Barrier; Brain; Cytochrome P-450 Enzyme System; Glucuronosyltransferase; Humans; Inactivation, Metabolic
PubMed: 29908109
DOI: No ID Found -
Expert Opinion on Drug Metabolism &... Jun 2022Hepatic drug metabolism is important in improving drug dosing strategies in sepsis. Pharmacokinetics in the critically ill population are severely altered due to changes... (Review)
Review
INTRODUCTION
Hepatic drug metabolism is important in improving drug dosing strategies in sepsis. Pharmacokinetics in the critically ill population are severely altered due to changes in absorption, distribution, excretion and metabolization. Hepatic drug metabolism might be altered due to changes in hepatic blood flow, drug metabolizing protein availability, and protein binding. The purpose of this review is to examine evidence on whether hepatic drug metabolism is significantly affected in septic patients, and to provide insights in the need for future research.
AREAS COVERED
This review describes the effect of sepsis on hepatic drug metabolism in humans. Clinical trials, pathophysiological background information and example drug groups are further discussed. The literature search has been conducted in Embase, Medline ALL Ovid, and Cochrane CENTRAL register of trials.
EXPERT OPINION
Limited research has been conducted on drug metabolism in the sepsis population, with some trials having researched healthy individuals using endotoxin injections. Notwithstanding this limitation, hepatic drug metabolism seems to be decreased for certain drugs in sepsis. More research on the pharmacokinetic behavior of hepatic metabolized drugs in sepsis is warranted, using inflammatory biomarkers, hemodynamic changes, mechanical ventilation, organ support, and catecholamine infusion as possible confounders.
Topics: Critical Illness; Humans; Liver; Sepsis
PubMed: 35912845
DOI: 10.1080/17425255.2022.2106215