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Critical Reviews in Oncology/hematology Jul 2023Metabolic reprogramming is one of the important characteristics of cancer and is a key process leading to malignant proliferation, tumor development and treatment... (Review)
Review
Metabolic reprogramming is one of the important characteristics of cancer and is a key process leading to malignant proliferation, tumor development and treatment resistance. A variety of therapeutic drugs targeting metabolic reaction enzymes, transport receptors, and special metabolic processes have been developed. In this review, we investigate the characteristics of multiple metabolic changes in cancer cells, including glycolytic pathways, lipid metabolism, and glutamine metabolism changes, describe how these changes promote tumor development and tumor resistance, and summarize the progress and challenges of therapeutic strategies targeting various links of tumor metabolism in combination with current study data.
Topics: Humans; Glycolysis; Neoplasms; Energy Metabolism; Lipid Metabolism
PubMed: 37236409
DOI: 10.1016/j.critrevonc.2023.104037 -
Current Drug Metabolism 2021Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of... (Review)
Review
BACKGROUND
Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of drug-metabolizing enzymes may affect the effectiveness and safety of pharmacotherapy of infections and inflammatory conditions.
OBJECTIVE
In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity and kinetics in rodents and humans.
RESULTS
An extensive literature review indicated that infection by Plasmodium spp consistently decreased the activity of hepatic Cytochrome P450s and phase-2 enzymes as well as the clearance of a variety of drugs in mice (lethal and non-lethal) and rat models of malaria. Malaria-induced CYP2A5 activity in the mouse liver was an exception. Except for paracetamol, pharmacokinetic trials in patients during acute malaria and in convalescence corroborated rodent findings. Trials showed that, in acute malaria, clearance of quinine, primaquine, caffeine, metoprolol, omeprazole, and antipyrine is slower and that AUCs are greater than in convalescent individuals.
CONCLUSION
Notwithstanding the differences between rodent models and human malaria, studies in P. falciparum and P. vivax patients confirmed rodent data showing that CYP-mediated clearance of antimalarials and other drugs is depressed during the symptomatic disease when rises in levels of acute-phase proteins and inflammatory cytokines occur. Evidence suggests that inflammatory cytokines and the interplay between malaria-activated NF-kB-signaling and cell pathways controlling phase 1/2 enzyme genes transcription mediate drug metabolism changes. The malaria-induced decrease in drug clearance may exacerbate drug-drug interactions, and the occurrence of adverse drug events, particularly when patients are treated with narrow-margin-of-safety medicines.
Topics: Animals; Antimalarials; Cytochrome P-450 Enzyme System; Drug Elimination Routes; Humans; Inactivation, Metabolic; Malaria; Metabolic Clearance Rate; Rodentia
PubMed: 33397251
DOI: 10.2174/1389200221999210101232057 -
Phytotherapy Research : PTR Aug 2022Natural compounds (NPs) have historically made a major contribution to pharmacotherapy in various diseases and drug discovery. In the past decades, studies on gut... (Review)
Review
Natural compounds (NPs) have historically made a major contribution to pharmacotherapy in various diseases and drug discovery. In the past decades, studies on gut microbiota have shown that the efficacy of NPs can be affected by the interactions between gut microbiota and NPs. On one hand, gut microbiota can metabolize NPs. On the other hand, NPs can influence the metabolism and composition of gut microbiota. Among gut microbiota metabolites, bile acids (BAs) have attracted widespread attention due to their effects on the body homeostasis and the development of diseases. Studies have also confirmed that NPs can regulate the metabolism of BAs and ultimately regulate the physiological function of the body and disease progresses. In this review, we comprehensively summarize the interactions among NPs, gut microbiota, and BAs. In addition, we also discuss the role of microbial BAs metabolism in understanding the toxicity and efficacy of NPs. Furthermore, we present personal insights into the future research directions of NPs and BAs.
Topics: Bile Acids and Salts; Gastrointestinal Microbiome; Homeostasis; Lipid Metabolism
PubMed: 35701855
DOI: 10.1002/ptr.7517 -
Clinical Pharmacology and Therapeutics Aug 2022Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug-metabolizing enzymes and transporters (DMETs) in humans.... (Review)
Review
Inflammation is a possible cause of variability in drug response and toxicity due to altered regulation in drug-metabolizing enzymes and transporters (DMETs) in humans. Here, we evaluate the clinical and in vitro evidence on inflammation-mediated modulation of DMETs, and the impact on drug metabolism in humans. Furthermore, we identify and discuss the gaps in our current knowledge. A systematic literature search on PubMed, Embase, and grey literature was performed in the period of February to September 2020. A total of 203 papers was included. In vitro studies in primary human hepatocytes revealed strong evidence that CYP3A4 is strongly downregulated by inflammatory cytokines IL-6 and IL-1β. CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were downregulated to a lesser extent. In clinical studies, acute and chronic inflammatory diseases were observed to cause downregulation of CYP enzymes in a similar pattern. However, there is no clear correlation between in vitro studies and clinical studies, mainly because most in vitro studies use supraphysiological cytokine doses. Moreover, clinical studies demonstrate considerable variability in terms of methodology and inconsistencies in evaluation of the inflammatory state. In conclusion, we find inflammation and pro-inflammatory cytokines to be important factors in regulation of drug-metabolizing enzymes and transporters. The observed downregulation is clinically relevant, and we emphasize caution when treating patients in an inflammatory state with narrow therapeutic index drugs. Further research is needed to identify the full extent of inflammation-mediated changes in DMETs and to further support personalized medicine.
Topics: Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Cytokines; Humans; Inactivation, Metabolic; Inflammation
PubMed: 34605009
DOI: 10.1002/cpt.2432 -
International Journal of Molecular... Jan 2023RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique... (Review)
Review
RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique targets and prolonged pharmacological effects. Their absorption, distribution, metabolism, and excretion (ADME) have important clinical im-plications, but their pharmacokinetic properties have not been fully understood. Most RNA therapeutics have structural modifications to prevent rapid elimination from the plasma and are administered intravenously or subcutaneously, with some exceptions, for effective distribution to target organs. Distribution of drugs into tissues depends on the addition of a moiety that can be transported to the target and RNA therapeutics show a low volume of distribution because of their molecular size and negatively-charged backbone. Nucleases metabolize RNA therapeutics to a shortened chain, but their metabolic ratio is relatively low. Therefore, most RNA therapeutics are excreted in their intact form. This review covers not only ADME features but also clinical pharmacology data of the RNA therapeutics such as drug-drug interaction or population pharmacokinetic analyses. As the market of RNA therapeutics is expected to rapidly expand, comprehensive knowledge will contribute to interpreting and evaluating the pharmacological properties.
Topics: Drug Interactions; Chemical Phenomena; Biological Transport; Pharmacokinetics
PubMed: 36614189
DOI: 10.3390/ijms24010746 -
Drug Metabolism Reviews Nov 2022Aldehyde oxidase (AO) has garnered curiosity as a non-CYP metabolizing enzyme in drug development due to unexpected consequences such as toxic metabolite generation and... (Review)
Review
Aldehyde oxidase (AO) has garnered curiosity as a non-CYP metabolizing enzyme in drug development due to unexpected consequences such as toxic metabolite generation and high metabolic clearance resulting in the clinical failure of new drugs. Therefore, poor AO mediated clearance prediction in preclinical nonhuman species remains a significant obstacle in developing novel drugs. Various isoforms of AO, such as , and exist across species, and different AO activity among humans influences the AO mediated drug metabolism. Therefore, carefully considering the unique challenges is essential in developing successful AO substrate drugs. The to extrapolation underpredicts AO mediated drug clearance due to the lack of reliable representative animal models, substrate-specific activity, and the discrepancy between absolute concentration and activity. An tool to extrapolate clearance using a yard-stick approach is provided to address the underprediction of AO mediated drug clearance. This approach uses a range of well-known AO drug substrates as calibrators for qualitative scaling new drugs into low, medium, or high clearance category drugs. So far, investigations on chimeric mice with humanized livers (humanized mice) have predicted AO mediated metabolism to the best extent. This review addresses the critical aspects of the drug discovery stage for AO metabolism studies, challenges faced in drug development, approaches to tackle AO mediated drug clearance's underprediction, and strategies to decrease the AO metabolism of drugs.
Topics: Humans; Animals; Mice; Aldehyde Oxidase; Metabolic Clearance Rate; Drug Discovery; Liver; Drug Development; Aldehyde Oxidoreductases
PubMed: 36369949
DOI: 10.1080/03602532.2022.2144879 -
Progress in Biophysics and Molecular... May 2023Glycometabolism is well known for its roles as the main source of energy, which mainly includes three metabolic pathways: oxidative phosphorylation, glycolysis and... (Review)
Review
Glycometabolism is well known for its roles as the main source of energy, which mainly includes three metabolic pathways: oxidative phosphorylation, glycolysis and pentose phosphate pathway. The orderly progress of glycometabolism is the basis for the maintenance of cardiovascular function. However, upon exposure to harmful stimuli, the intracellular glycometabolism changes or tends to shift toward another glycometabolism pathway more suitable for its own development and adaptation. This shift away from the normal glycometabolism is also known as glycometabolism reprogramming, which is commonly related to the occurrence and aggravation of cardiovascular diseases. In this review, we elucidate the physiological role of glycometabolism in the cardiovascular system and summarize the mechanisms by which glycometabolism drives cardiovascular diseases, including diabetes, cardiac hypertrophy, heart failure, atherosclerosis, and pulmonary hypertension. Collectively, directing GMR back to normal glycometabolism might provide a therapeutic strategy for the prevention and treatment of related cardiovascular diseases.
Topics: Humans; Cardiovascular Diseases; Glycolysis; Metabolic Networks and Pathways; Oxidative Phosphorylation; Cardiomegaly
PubMed: 36963725
DOI: 10.1016/j.pbiomolbio.2023.03.003 -
Current Opinion in Pediatrics Feb 2020In an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. Although... (Review)
Review
PURPOSE OF REVIEW
In an attempt to identify potential new therapeutic targets, efforts to describe the metabolic features unique to cancer cells are increasingly being reported. Although current standard of care regimens for several pediatric malignancies incorporate agents that target tumor metabolism, these drugs have been part of the therapeutic landscape for decades. More recent research has focused on the identification and targeting of new metabolic vulnerabilities in pediatric cancers. The purpose of this review is to describe the most recent translational findings in the metabolic targeting of pediatric malignancies.
RECENT FINDINGS
Across multiple pediatric cancer types, dependencies on a number of key metabolic pathways have emerged through study of patient tissue samples and preclinical modeling. Among the potentially targetable vulnerabilities are glucose metabolism via glycolysis, oxidative phosphorylation, amino acid and polyamine metabolism, and NAD metabolism. Although few agents have yet to move forward into clinical trials for pediatric cancer patients, the robust and promising preclinical data that have been generated suggest that future clinical trials should rationally test metabolically targeted agents for relevant disease populations.
SUMMARY
Recent advances in our understanding of the metabolic dependencies of pediatric cancers represent a source of potential new therapeutic opportunities for these diseases.
Topics: Amino Acids; Antineoplastic Agents; Child; Folic Acid; Glycolysis; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; NAD; Neoplasms; Oxidative Phosphorylation; Polyamines
PubMed: 31789976
DOI: 10.1097/MOP.0000000000000853 -
Xenobiotica; the Fate of Foreign... Jun 2020Temsirolimus, a derivative of sirolimus, exhibits potent antitumor properties. It was the goal of this study to identify yet unknown temsirolimus metabolites generated...
Temsirolimus, a derivative of sirolimus, exhibits potent antitumor properties. It was the goal of this study to identify yet unknown temsirolimus metabolites generated after incubation with human liver microsomes. Previously, 23-hydroxy-, 24-hydroxy, 12-hydroxy, hydroxy-piperidine and 27--desmethyl temsirolimus had been described.Metabolite structures were identified using high-resolution mass spectrometry, MS/iontrap (MS) and comparison of fragmentation patterns of the metabolites with those of temsirolimus and other known sirolimus derivatives. Moreover, enzyme kinetic parameters of temsirolimus metabolite formation as well as the contribution of individual recombinant cytochrome P450 (CYP) enzymes to temsirolimus metabolism were investigated.Human liver microsomes mainly hydroxylated and/or demethylated temsirolimus. The structures of the following metabolites were identified: -demethylated metabolites: 39--desmethyl, 16--desmethyl and 27--desmethyl temsirolimus; hydroxylated metabolites: hydroxy piperidine temsirolimus, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24-hydroxy, 25-hydroxy, 45/46-hydroxy and 49-hydroxy temsirolimus; demethylated-hydroxylated metabolites: 16--desmethyl, 24-hydroxy; 16--desmethyl, 23-hydroxy and 16--desmethyl 46-hydroxy temsirolimus; didemethylated metabolite: 27,39--didesmethyl temsirolimus; and dihydroxylated metabolite: 12,24-dihydroxy temsirolimus. It was confirmed that CYP3A4 represents the predominant enzyme responsible for temsirolimus metabolism. Moreover, CYP3A5 as well as CYP2C8 also showed significant activities especially resulting in the formation of 27--desmethyl, 25-hydroxy and hydroxy-piperidine temsirolimus.It is concluded that temsirolimus is metabolized to more than 20 metabolites, not counting metabolism the sirolimus pathway. Eighteen of these metabolites could be structurally identified using ion trap MS and high-resolution mass spectrometry. Moreover, the present study showed that, in addition to CYP3A4, metabolism CYP3A5 and CYP2C8 also represent significant metabolic pathways.
Topics: Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Humans; Hydroxylation; Mass Spectrometry; Metabolic Networks and Pathways; Microsomes, Liver; Sirolimus
PubMed: 31596164
DOI: 10.1080/00498254.2019.1678793