439 results found
Athersuch TJ, Antoine DJ, Boobis AR, et al., 2018, Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions: a perspective, Toxicology Research, ISSN: 2045-452X
After over 60 years of therapeutic use in the UK, paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (AM404) still a topic of debate. However, that the hepatotoxicity of APAP results from the production of the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI/NABQI) that can deplete glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of NAPQI provides a source of potential biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the microRNA miR-122 as well as mechanistic biomarkers associated with apoptosis, mitochondrial dysfunction, inflammation and tissue regeneration. Additionally, biomarkers of, and systems biology models for, glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to APAP-mediated toxicity. This perspective highlights some of the progress in current APAP-related research.
Bradshaw PR, Wilson ID, Gill RU, et al., 2018, Metabolic Hydrolysis of Aromatic Amides in Selected Rat, Minipig, and Human In Vitro Systems, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Theodoridis GA, Gika HG, Wilson ID, 2018, Preface
Triantafyllou E, Pop OT, Possamai LA, et al., 2018, MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure, GUT, Vol: 67, Pages: 333-347, ISSN: 0017-5749
Wilson CE, Dickie AP, Schreiter K, et al., 2018, The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice., Arch Toxicol
The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may r
Akingbasote JA, Foster AJ, Jones HB, et al., 2017, Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid, Toxicology Research, Vol: 6, Pages: 81-88, ISSN: 2045-452X
© The Royal Society of Chemistry. Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit no functional expression of hepatic cytochrome P450 (P450) when compared to wild type (WT) mice, but have normal hepatic and extrahepatic expression of other biotransformation enzymes. We have assessed the utility of HRN™ mice for investigation of the role of metabolic bioactivation in liver toxicity caused by the nonsteroidal anti-inflammatory drug (NSAID) fenclozic acid. In vitro studies revealed significant NADPH-dependent (i.e. P450-mediated) covalent binding of [ 14 C]-fenclozic acid to liver microsomes from WT mice and HRN™ mice, whereas no in vitro covalent binding was observed in the presence of the UDP-glucuronyltransferase cofactor UDPGA. Oral fenclozic acid administration did not alter the liver histopathology or elevate the plasma liver enzyme activities of WT mice, or affect their hepatic miRNA contents. Livers from HRN™ mice exhibited abnormal liver histopathology (enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration, necrosis, inflammatory cell infiltration) and plasma clinical chemistry (elevated alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities). Modest apparent improvements in these abnormalities were observed when HRN™ mice were dosed orally with fenclozic acid for 7 days at 100 mg kg −1 day −1 . Previously we observed more marked effects on liver histopathology and integrity in HRN™ mice dosed orally with the NSAID diclofenac for 7 days at 30 mg kg −1 day −1 . We conclude that HRN™ mice are valuable for assessing P450-related hepatic drug biotransformation, but not for drug toxicity studies due to underlying liver dysfunction. Nonetheless, HRN™ mice may provide novel insights into the role of inflammation in liver injury, thereby aiding its treatment.
Alexander JL, Wilson ID, Teare J, et al., 2017, Gut microbiota modulation of chemotherapy efficacy and toxicity., Nat Rev Gastroenterol Hepatol, Vol: 14, Pages: 356-365
Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.
Begou O, Gika HG, Wilson ID, et al., 2017, Hyphenated MS-based targeted approaches in metabolomics., Analyst, Vol: 142, Pages: 3079-3100
While global metabolic profiling (untargeted metabolomics) has been the center of much interest and research activity in the past few decades, more recently targeted metabolomics approaches have begun to gain ground. These analyses are, to an extent, more hypothesis-driven, as they focus on a set of pre-defined metabolites and aim towards their determination, often to the point of absolute quantification. The continuous development of the technological platforms used in these studies facilitates the analysis of large numbers of well-characterized metabolites present in complex matrices. The present review describes recent developments in the hyphenated chromatographic methods most often applied in targeted metabolomic/lipidomic studies (LC-MS/MS, CE-MS/MS, and GC-MS/MS), highlighting applications in the life and food/plant sciences. The review also underlines practical challenges-limitations that appear in such approaches.
Dickie AP, Wilson CE, Schreiter K, et al., 2017, The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice., Biochem Pharmacol, Vol: 135, Pages: 139-150
The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08μg/mL at 0.25-0.5h post-dose with an AUCinf of 1.74±0.52μgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08μg/mL at 0.25h post-dose with an AUCinf of 1.94±0.22μgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans.
Gika H, Theodoridis G, Rainville P, et al., 2017, Metabolic phenotyping (metabonomics/metabolomics) by liquid chromatography-mass spectrometry, Liquid Chromatography: Applications: Second Edition, Pages: 245-265, ISBN: 9780128053928
© 2017 Elsevier Inc. All rights reserved. Liquid chromatography-mass spectrometry (LC-MS, and variants such as supercritical fluid chromatography-mass spectrometry (SFC-MS)) is widely used to derive characteristic metabolic phenotypes using untargeted approaches to perform unbiased global metabolic profiling. Currently, applications in this area are mainly undertaken using reversed-phase (RP) separations, but hydrophilic interaction chromatography (HILIC) and less frequently ion-pair (IP) LC are also used for polar compounds that are poorly retained by such methods. Following the introduction of ultra (high) performance liquid chromatography (U(H)PLC), there has been an increasing trend in metabonomic/metabolomic applications for it to supplant traditional HPLC formats with the benefits of rapid, sensitive, and high-resolution separations, leading to increased metabolome coverage. In addition to these "conventional" approaches, there are continuing investigations of alternative methods involving miniaturization and the application of supercritical HP- and UHP-chromatographic separations.
Glymenaki M, Barnes A, Hagan SO, et al., 2017, Stability in metabolic phenotypes and inferred metagenome profiles before the onset of colitis-induced inflammation, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Gray N, Zia R, King A, et al., 2017, High-Speed Quantitative UPLC-MS Analysis of Multiple Amines in Human Plasma and Serum via Precolumn Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate: Application to Acetaminophen-Induced Liver Failure, ANALYTICAL CHEMISTRY, Vol: 89, Pages: 2478-2487, ISSN: 0003-2700
P Dickie A, Wilson CE, Schreiter K, et al., 2017, Lumiracoxib metabolism in male C57bl/6J mice: characterisation of novel in vivo metabolites., Xenobiotica, Vol: 47, Pages: 538-546
1. The pharmacokinetics and metabolism of lumiracoxib in male C57bl/6J mice were investigated following a single oral dose of 10 mg/kg. 2. Lumiracoxib achieved peak observed concentrations in the blood of 1.26 + 0.51 μg/mL 0.5 h (0.5-1.0) post-dose with an AUCinf of 3.48 + 1.09 μg h/mL. Concentrations of lumiracoxib then declined with a terminal half-life of 1.54 + 0.31 h. 3. Metabolic profiling showed only the presence of unchanged lumiracoxib in blood by 24 h, while urine, bile and faecal extracts contained, in addition to the unchanged parent drug, large amounts of hydroxylated and conjugated metabolites. 4. No evidence was obtained in the mouse for the production of the downstream products of glutathione conjugation such as mercapturates, suggesting that the metabolism of the drug via quinone-imine generating pathways is not a major route of biotransformation in this species. Acyl glucuronidation appeared absent or a very minor route. 5. While there was significant overlap with reported human metabolites, a number of unique mouse metabolites were detected, particularly taurine conjugates of lumiracoxib and its oxidative metabolites.
Pickup K, Martin S, Partridge EA, et al., 2017, Acute liver effects, disposition and metabolic fate of [14C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J mice., Arch Toxicol, Vol: 91, Pages: 2643-2653
The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).
Rainville PD, Wilson ID, Nicholson JK, et al., 2017, Ion mobility spectrometry combined with ultra performance liquid chromatography/mass spectrometry for metabolic phenotyping of urine: Effects of column length, gradient duration and ion mobility spectrometry on metabolite detection, ANALYTICA CHIMICA ACTA, Vol: 982, Pages: 1-8, ISSN: 0003-2670
© 2017 Elsevier Ltd. All rights reserved. Genetically humanized mice for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging as promising in vivo models for improved prediction of the pharmacokinetic, drug-drug interaction, and safety characteristics of compounds in humans. This is an overview on the genetically humanized and chimeric liver-humanized mouse models, which are illustrated with examples of their utility in drug metabolism and toxicity studies. The models are compared to give guidance for selection of the most appropriate model by highlighting advantages and disadvantages to be carefully considered when used for studies in drug discovery and development.
Swann JR, Garcia-Perez I, Braniste V, et al., 2017, Application of H-1 NMR spectroscopy to the metabolic phenotyping of rodent brain extracts: A metabonomic study of gut microbial influence on host brain metabolism, JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, Vol: 143, Pages: 141-146, ISSN: 0731-7085
Akingbasote JA, Foster AJ, Wilson I, et al., 2016, Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice., Arch Toxicol, Vol: 90, Pages: 853-862
Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [(14)C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [(14)C]-diclofenac was incubated with HRN™ mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN™ mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN™ mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN™ mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN™ mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN™ mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.
Gika HG, Zisi C, Theodoridis G, et al., 2016, Protocol for quality control in metabolic profiling of biological fluids by U(H)PLC-MS., J Chromatogr B Analyt Technol Biomed Life Sci, Vol: 1008, Pages: 15-25
The process of untargeted metabolic profiling/phenotyping of complex biological matrices, i.e., biological fluids such as blood plasma/serum, saliva, bile, and tissue extracts, provides the analyst with a wide range of challenges. Not the least of these challenges is demonstrating that the acquired data are of "good" quality and provide the basis for more detailed multivariate, and other, statistical analysis necessary to detect, and identify, potential biomarkers that might provide insight into the process under study. Here straightforward and pragmatic "quality control (QC)" procedures are described that allow investigators to monitor the analytical processes employed for global, untargeted, metabolic profiling. The use of this methodology is illustrated with an example from the analysis of human urine where an excel spreadsheet of the preprocessed LC-MS output is provided with embedded macros, calculations and visualization plots that can be used to explore the data. Whilst the use of these procedures is exemplified on human urine samples, this protocol is generally applicable to metabonomic/metabolomic profiling of biofluids, tissue and cell extracts from many sources.
Goveia J, Pircher A, Conradi L-C, et al., 2016, Meta-analysis of clinical metabolic profiling studies in cancer: challenges and opportunities., EMBO Mol Med, Vol: 8, Pages: 1134-1142
Cancer cell metabolism has received increasing attention. Despite a boost in the application of clinical metabolic profiling (CMP) in cancer patients, a meta-analysis has not been performed. The primary goal of this study was to assess whether public accessibility of metabolomics data and identification and reporting of metabolites were sufficient to assess which metabolites were consistently altered in cancer patients. We therefore retrospectively curated data from CMP studies in cancer patients published during 5 recent years and used an established vote-counting method to perform a semiquantitative meta-analysis of metabolites in tumor tissue and blood. This analysis confirmed well-known increases in glycolytic metabolites, but also unveiled unprecedented changes in other metabolites such as ketone bodies and amino acids (histidine, tryptophan). However, this study also highlighted that insufficient public accessibility of metabolomics data, and inadequate metabolite identification and reporting hamper the discovery potential of meta-analyses of CMP studies, calling for improved standardization of metabolomics studies.
Gray N, Adesina-Georgiadis K, Chekmeneva E, et al., 2016, Development of a Rapid Microbore Metabolic Profiling (RAMMP) UPLC-MS Approach for High-Throughput Phenotyping Studies., Analytical Chemistry, Vol: 88, Pages: 5742-5751, ISSN: 0003-2700
A rapid gradient microbore UPLC-MS method has been developed to provide a high-throughput analytical platform for the metabolic phenotyping of urine from large sample cohorts. The rapid microbore metabolic profiling (RAMMP) approach was based on scaling a conventional reversed-phase UPLC-MS method for urinary profiling from 2.1 x 100 mm columns to 1 x 50 mm columns, increasing the linear velocity of the solvent, and decreasing the gradient time to provide an analysis time of 2.5 min/sample. Comparison showed that conventional UPLC-MS and rapid gradient approaches provided peak capacities of 150 and 50 respectively, with the conventional method detecting approximately 19,000 features compared to the ca. 6000 found using the rapid gradient method. Similar levels of repeatability were seen for both methods. Despite the reduced peak capacity and the reduction in ions detected, the RAMMP method was able to achieve similar levels of group discrimination as conventional UPLC-MS when applied to rat urine samples obtained from investigative studies on the effects of acute 2-bromophenol and chronic acetaminophen administration. When compared to a direct infusion MS method of similar analysis time the RAMMP method provided superior selectivity. The RAMMP approach provides a robust and sensitive method that is well suited to high-throughput metabonomic analysis of complex mixtures such as urine combined with a five fold reduction in analysis time compared with the conventional UPLC-MS method.
Kyriakides M, Maitre L, Stamper BD, et al., 2016, Comparative metabonomic analysis of hepatotoxicity induced by acetaminophen and its less toxic meta-isomer, ARCHIVES OF TOXICOLOGY, Vol: 90, Pages: 3073-3085, ISSN: 0340-5761
Lindon JC, Wilson ID, 2016, The development of metabolic phenotyping-a historical perspective, Metabolic Phenotyping in Personalized and Public Healthcare, Pages: 17-48, ISBN: 9780128003442
© 2016 Elsevier Inc. All rights reserved. In this chapter, a broad history of the field of metabolic phenotyping (also known as metabonomics and metabolomics) is presented. Largely overlooked pioneering studies from the 1960s and 1970s are described, and this is then followed by a description of the main development of the field using modern analytical chemistry techniques, mainly nuclear magnetic resonance spectroscopy and mass spectrometry. The use of multivariate statistics and related methods that are used to interpret the complex data led to the dramatic progress made in the field. The expansion into animal models of disease and drug toxicity is described, and the current explosive increase in large-scale epidemiologic studies at one end of the range and high precision clinical studies for stratified medicine at the other is discussed. This has led to the concept of dedicated phenome centers for metabolic phenotyping and the current state of the art is explained.
Michopoulos F, Karagianni N, Whalley NM, et al., 2016, Targeted Metabolic Profiling of the Tg197 Mouse Model Reveals Itaconic Acid as a Marker of Rheumatoid Arthritis., J Proteome Res, Vol: 15, Pages: 4579-4590
Rheumatoid arthritis is a progressive, highly debilitating disease where early diagnosis, enabling rapid clinical intervention, would provide obvious benefits to patients, healthcare systems, and society. Novel biomarkers that enable noninvasive early diagnosis of the onset and progression of the disease provide one route to achieving this goal. Here a metabolic profiling method has been applied to investigate disease development in the Tg197 arthritis mouse model. Hind limb extract profiling demonstrated clear differences in metabolic phenotypes between control (wild type) and Tg197 transgenic mice and highlighted raised concentrations of itaconic acid as a potential marker of the disease. These changes in itaconic acid concentrations were moderated or indeed reversed when the Tg197 mice were treated with the anti-hTNF biologic infliximab (10 mg/kg twice weekly for 6 weeks). Further in vitro studies on synovial fibroblasts obtained from healthy wild-type, arthritic Tg197, and infliximab-treated Tg197 transgenic mice confirmed the association of itaconic acid with rheumatoid arthritis and disease-moderating drug effects. Preliminary indications of the potential value of itaconic acid as a translational biomarker were obtained when studies on K4IM human fibroblasts treated with hTNF showed an increase in the concentrations of this metabolite.
Scheer N, Wilson ID, 2016, A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity, DRUG DISCOVERY TODAY, Vol: 21, Pages: 250-263, ISSN: 1359-6446
Sen A, Knappy C, Lewis MR, et al., 2016, Analysis of polar urinary metabolites for metabolic phenotyping using supercritical fluid chromatography and mass spectrometry, JOURNAL OF CHROMATOGRAPHY A, Vol: 1449, Pages: 141-155, ISSN: 0021-9673
Weidolf L, Wilson ID, 2016, Understanding drug metabolism in humans: In vivo, Metabolite Safety in Drug Development, Pages: 141-176, ISBN: 9781118949689
© 2016 by John Wiley & Sons, Inc. All rights reserved. This chapter describes the strategies and tactics that can be used in in vivo studies to help provide the required knowledge and understanding of in vivo metabolism, especially in humans, to provide the best outcomes for candidate drugs as they progress through development and toward clinical use. A final preparation for the human radiolabeled study is to perform a quantitative tissue distribution study which is most often satisfied by performing a quantitative whole-body autoradiography (QWBA) study. Where metabolism is thought to be primarily undertaken in the liver, the chimeric humanized mouse model may represent a very useful means of investigating human-specific drug metabolism. Transgenic mice have been developed that are humanized in the liver (or gut) for the aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPARa), and pregnane X receptor (PXR), all of which have importance in drug metabolism.
Wilson ID, Nicholson JK, 2016, Gut microbiome interactions with drug metabolism, efficacy, and toxicity., Transl Res, Vol: 179, Pages: 204-222
The gut microbiota has both direct and indirect effects on drug and xenobiotic metabolisms, and this can have consequences for both efficacy and toxicity. Indeed, microbiome-driven drug metabolism is essential for the activation of certain prodrugs, for example, azo drugs such as prontosil and neoprontosil resulting in the release of sulfanilamide. In addition to providing a major source of reductive metabolizing capability, the gut microbiota provides a suite of additional reactions including acetylation, deacylation, decarboxylation, dehydroxylation, demethylation, dehalogenation, and importantly, in the context of certain types of drug-related toxicity, conjugates hydrolysis reactions. In addition to direct effects, the gut microbiota can affect drug metabolism and toxicity indirectly via, for example, the modulation of host drug metabolism and disposition and competition of bacterial-derived metabolites for xenobiotic metabolism pathways. Also, of course, the therapeutic drugs themselves can have effects, both intended and unwanted, which can impact the health and composition of the gut microbiota with unforeseen consequences.
Coen M, Wilson ID, 2015, Preclinical Drug Efficacy and Safety Using NMR Spectroscopy, EMAGRES, Vol: 4, Pages: 277-287, ISSN: 2055-6101
Deda O, Gika HG, Wilson ID, et al., 2015, An overview of fecal sample preparation for global metabolic profiling., J Pharm Biomed Anal, Vol: 113, Pages: 137-150
The global metabolic profiling of feces represents a challenge for both analytical chemistry and biochemistry standpoints. As a specimen, feces is complex, not homogenous and rich in macromolecules and particulate, non-digested, matter that can present problems for analytical systems. Further to this, the composition of feces is highly dependent on short-term dietary factors whilst also representing the primary specimen where co-metabolism of the host organism and the gut-microbiota is expressed. Thus the presence and the content of metabolites can be a result of host metabolism, gut microbiota metabolism or co-metabolism. Successful sample preparation and metabolite analysis require that the methodology applied for sample preparation is adequate to compensate for the highly variable nature of the sample in order to generate useful data and provide insight to ongoing biochemical processes, thereby generating hypotheses. The current practices for processing fecal samples for global metabolic profiling are described with emphasis on critical aspects in sample preparation: e.g., homogenization, filtration, centrifugation, solvent extraction and so forth and also conditions/parameter selection are discussed. The different methods applied for feces processing prior to metabolite analysis are summarized and illustrated using selected examples to highlight the effect of sample preparation on the metabolic profile obtained.
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