The Study of Drug Metabolism Using Radiotracers
Graham Lappin, Simon Temple in Radiotracers in Drug Development, 2006
Metabolic pathways are interpreted as a series of distinct chemical reactions, each catalyzed by an individual enzyme. Perhaps this interpretation is a consequence of the use of radiotracers in the elucidation of the pathway, as the intention is to isolate the reaction from the complexity of its surroundings. In reality, however, xenobiotics are metabolized by semispecific enzymes, and therefore pathways are better represented as multidimensional matrices rather than a series of linear steps. Furthermore, xenobiotics are subject to active transport mechanisms. All these effects within the cell will be interrelated in respect to the final metabolic products.29 Here, like in the vast majority of other publications, metabolic pathways are shown as flat, two-dimensional depictions; to do otherwise would only confuse. Bear in mind, however, the reality is infinitely more complicated.
ENZYME-CATALYZED REACTIONS
David M. Gibson, Robert A. Harris in Metabolic Regulation in Mammals, 2001
In animal (eukaryotic) cells there are in the order of a thousand distinct organic chemical reactions. With few exceptions all of these are linked together in chains of successive coupled reactions called metabolic pathways. One reaction is couplcd to a second through a shared common intermediate. A reaction with two products can be coupled to two other reactions forming a "branch point" (often the case when one product is recycled through a second metabolic pathway). Coupling of reactions permits an cndergonic: reaction (suc h as a synthetic step), which is impossible in isolation, to take place. If a sufficiently strong exergonic reaction is coupled to an cndergonic reaction (through a common intermediate) the combination can be exergonic, namely the total AG' value is negative. This will depend on their respective rcactant and product concentrations and the values of the two standard free energy constants. In this sense a whole scries of reactions can be coupled together. Indeed a powerful energy yielding pathway such as the oxidation of glucose to CO, and H,0 can drive a host of cndergonic synthetic steps, such as protein synthesis, through coupling intermediates. Every energy-requiring process in the cell (referred to as metabolic-demand) is ultimately linked to oxidative generators so that, in summation, the entire activity of a cell, its characterization as a "viable" cell, is a spontaneous exergonic process.
Pharmacokinetic-Pharmacodynamic Correlations of Corticosteroids
Hartmut Derendorf, Günther Hochhaus in Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Pharmacokinetic models for this reversible metabolic pathway have been described.76,77 No dose-dependent differences are observed5 when the kinetic parameters of P are normalized for protein or transcortin-free fractions. Therefore, the kinetic parameters of P are often based on the free drug concentration.5,45,78 Moreover, P disposition is complicated by diurnal variations.74,79 About 30% higher plasma concentrations were found after drug administration in the morning in comparison to the same dose given in the evening. Prednisolone is excreted in urine as oxidated metabolites, PR (2 to 5%) and P (11 to 24%).5,52,80 A plasma half-life of 3 to 4 h has been observed for PR.5,81,82 The low transcortin affinity excludes saturable protein binding as an explanation for the nonlinear kinetics of this compound.6,66,83 It has a total body clearance of 11 to 18 l/h and a Vd of 60 to 75 l.81 Prednisolone hemisuccinate also shows nonlinear kinetics with a decreased CLtot after high plasma concentrations.22 Average PHS doses (75 mg) lead to 0.8% unchanged hemisuccinate in urine. After high doses (1200 mg) about 8% of the administered ester is uncleaved in urine, indicating an incomplete conversion of prodrug and/or a saturable renal tubular reabsorption mechanism.22 A total body clearance of 69 l/h and a Vd of 28 l have been observed after medium PHS doses.22,58
Integrative omics - from data to biology
Published in Expert Review of Proteomics, 2018
Hassan Dihazi, Abdul R. Asif, Tim Beißbarth, Rainer Bohrer, Kirstin Feussner, Ivo Feussner, Olaf Jahn, Christof Lenz, Andrzej Majcherczyk, Bernhard Schmidt, Kerstin Schmitt, Henning Urlaub, Oliver Valerius
Metabolic pathways in a biological system are tailored to satisfy its needs. In his research, Asaph Aharoni uses integrated omics approaches to unravel networks of genes and proteins involved in the regulation of plant metabolism [9]. In his talk, he highlighted several advanced tools for studying metabolomes and the advantage of integrating metabolomics, genetics and informatics data. The advantage of the combination of the different tools in a single study was shown in investigations combining coexpression analysis and metabolomics to unravel the secondary metabolism of nightshades (Solanaceae). The second talk was given by Alexander Karabatsiakis [10]. He highlighted the advantage of combining metabolomics with lipidomics data to investigate the mechanisms underlying the physical and mental health problems in adults who suffer from childhood maltreatment (CM). The data presented showed that with this integrative omics approach it was possible to identify markers of inflammation and oxidative stress, which allowed to differentiate between individuals with and without CM. Moreover, the data presented suggest pathways that may be involved in the effect of CM on health and disease. The third talk provided new insights into approaches that combine different omics workflows and was given by Kirstin Feussner, representing the Göttingen Metabolomics & Lipidomics Platform (GöMLP, weblink). Here, nontargeted metabolomics combined with lipidomics, hormone analyses, and transcriptomics data by the software tool MarVis gave insights into plant stress adaptation and allowed to identify new wound-related markers and pathways.
Repair mechanism of Wuwei Fuzheng Yijing formula in di-2-ethylhexyl phthalate-induced sperm DNA fragmentation in mice
Published in Pharmaceutical Biology, 2022
Chenming Zhang, Shiqi Wang, Zulong Wang, Qi Zhang, Rubing Chen, Hao Zhang, Zhong Hua, Sicheng Ma
Our combined transcriptome and proteome analysis found that the repairing effect of WFY on DEHP-induced sperm DNA damage was related to the metabolic pathway and the PI3K/Akt pathway. The metabolic pathway involves many functional activities, and changes in the metabolic pathway have been found in many diseases. The PI3K/Akt pathway is correlated with oxidative damage and DNA integrity. Activation of the PI3K/Akt signalling pathway leads to a direct interaction between phosphorylated MDM2 and p53 degradation. P53 degradation causes p53-dependent DNA damage checkpoint or repair dysfunction and ultimately results in the accumulation of DNA damage in sperm (Xian et al. 2017). Although no other Chinese herbal formulas have been found to repair sperm DNA damage through the PI3K/Akt pathway, some Chinese herbal formulas were able to improve other sperm parameters (such as sperm concentration and motility) through the PI3K/Akt pathway, possibly by promoting spermatogenic cell proliferation and inhibiting apoptosis (Chen et al. 2021).
Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment
Published in Drug Delivery, 2023
Ling Zhang, Bing-Zhong Zhai, Yue-Jin Wu, Yin Wang
Cancer is reported as the major cause of premature death in China and other developed nations (Bray et al., 2021). GLOBOCAN 2020 reported that there were 19,292,789 cases of cancer and 9,958,133 deaths from cancer worldwide in 2020 (Sung et al., 2021). Since 2000, the prevalence and mortality of cancer in China have risen gradually (Wei et al., 2020). Cancer cells are distinguished by their uncontrolled proliferation, transformation, and migration to other parts of the body, as well as their propensity to harm normal cells (Suresh, 2007). Cancer cells acquire atypical metabolic pathways to get energy and raw materials for achieving the energy requirements for vigorous cell growth and migration. The reason cancer cells acquire energy via atypical metabolic pathways is that their metabolism is more vigorous than that of normal cells (Zanotelli et al., 2021). Multiple carcinogenic signaling pathways regulate three primary metabolic pathways in cancer cells. These metabolic pathways include lipid, amino acid, and glucose metabolism (Dzobo et al., 2020). The distinctive metabolism of cancer cells implies that changes at the metabolic level are essential for the development and genesis of cancer cells.
Related Knowledge Centers
- Biochemistry
- Catalysis
- Chemical Reaction
- Enzyme
- Enzyme Catalysis
- Metabolic Intermediate
- Metabolite
- Reagent
- Cell
- Product