scholarly journals Drug Metabolism in Drug Discovery and Preclinical Development

2021 ◽  
Author(s):  
Benjamin Mann ◽  
Roger Melton ◽  
David Thompson

Drug metabolism or more generally, xenobiotic metabolism, is the biotransformation of exogenous compounds by living organisms, usually through specialized enzymatic systems. The metabolism of experimental therapeutics is an important aspect of pharmacology and translational medicine as the rate and the interindividual variability of drug metabolism can determine the duration and/or efficacy of a drug’s pharmacologic action. Since the introduction of metabolites in safety testing guidance by the Food and Drug Administration, major changes have occurred in the experimental methods for the identification and quantification of metabolites, evaluation of metabolites, and the timing of critical nonclinical studies to generate this information.

2004 ◽  
Vol 01 (04) ◽  
pp. 711-741 ◽  
Author(s):  
SEE-KIONG NG ◽  
SOON-HENG TAN

The ongoing genomics and proteomics efforts have helped identify many new genes and proteins in living organisms. However, simply knowing the existence of genes and proteins does not tell us much about the biological processes in which they participate. Many major biological processes are controlled by protein interaction networks. A comprehensive description of protein–protein interactions is therefore necessary to understand the genetic program of life. In this tutorial, we provide an overview of the various current high-throughput methods for discovering protein–protein interactions, covering both the conventional experimental methods and new computational approaches.


2000 ◽  
Vol 19 (4) ◽  
pp. 257-260 ◽  
Author(s):  
U Liminga

A review of preclinical assessment reports on immuno-modulatory biopharmaceuticals submitted to the Eur-opean Agency for Evaluation of Medicinal Products from 1995 to the middle of 1999 was conducted. Questions regarding the rationale for the preclinical development programmes were often put to the applicants. Effects mediated via changes of the immune function, including risks of reproductive toxicity and tumorigenicity, were of Background: European Union regulatory review process In 1995, the “New System” for authorisation of medicinal products in the European Union (EU) was introduced. At the same time, the European Agency for Evaluation of Medicinal Products (EMEA) was created. The EMEA is the permanent secretariat for the Committee for Proprietary Medicinal Products (CPMP), which is a scientific committee responsible for human medicinal products. Since 1995, it has been possible to submit a single EU marketing authorisation application (MAA) to the EMEA, which is reviewed following a predefined procedure with set time frames. The CPMP has two representatives from each member state and for each MAA, a rapporteur and a co-rapporteur are assigned from this represen-tation. The primary evaluation is performed by assessor teams, consisting of European experts from the national agencies and academia, who are engaged by the rapporteurs. These evaluations are subse-quently commented on by experts from the other member states. Within 120 days of active review time, the CPMP agrees on a “List of Questions,” which is sent to the applicant. The applicant's responses to the “List of Questions” are assessed by both rapporteur teams, and their joint *Correspondence: Dr U Liminga, Medical Products Agency, Box 26, S-751 03, Uppsala, Sweden particular concern. This review indicates the need to further develop methods for safety testing of immunomo-dulatory biopharmaceuticals.


2021 ◽  
Vol 11 (40) ◽  
pp. 185-186
Author(s):  
Elzbieta Malarczyk

Introduction: The fungal and bacterial materials are very useful for testing the influence of low and very low doses of low molecular phenolic effectors on enzymatic system of phenoloxidases when they are incubated together in the reaction space. Aim: Searching for the model useful biological systems to study the action of diluted low molecular substances on living organisms, which is based on common physical and biochemical analytical procedures. Methods: The fungal and actinomycetal bacterial materials from laboratory cultures as a source of common phenoloxidases, laccase, peroxidase and O-demethylase as well as the pure plant peroxidase were used in experiments described earlier [1-5]. Subsequent dilutions of low molecular phenolic metabolites, appropriate for studied enzymatic systems, prepared in 75% ethanol in the proportion of 1:100 (centesimal) and dynamized by shaking in accordance with homeopathic procedures were prepared in our laboratory. During experiments with bacterial and fungal materials and a pure plant peroxidase, which were incubated together with subsequent dilutions of proper phenolic effector, different analytic methods were used including a gel (PAGE) [4] and capillary (MEKCE) electrophoresis [5], spectral and colorimetric methods [1,2,3] as well as the electron microscopy [5]. Results: In the light of presented data [1-5], the incubation of biological material with diluted phenolic effectors induces various effects on tested enzyme activity. It changed in sinusoidal manner with an gradual growth of dilution rate of tested effectors, which was distinctly visible on the diagram when the number of dilutions was localized on abscissa and biological activity on the ordinate. Exemplary results of the chosen experiments will be presented. For tested enzymes: laccase, peroxidase and O-demethylase, the distance between maximal points of enzymatic activity, shown on a sine curve, repeats more often every 10 subsequent centesimal dilutions. Along with the extension of incubation period the displacement of maximal and minimal points on curve were noticed, which revealed a dynamic aspect of studied phenomenon. Conclusions: Fungal and bacterial cells seem to be a very convenient material for studying the action of diluted metabolites on enzymatic systems because their popular presence in environment. Results of all experiments confirmed the same nature of the mentioned observations. Because other authors had similar conclusion concerning human [6,7] and plant materials [8,9], the described relations seem to be common in natural world. It could also be stressed that the therapeutic effect of homeopathic remedies could be based on the mechanism described above and it is highly probable that it leads to a normalisation of disturbed enzyme systems in the living organisms.


2021 ◽  
Vol 22 ◽  
Author(s):  
Abhinav Parashar ◽  
Kelath Murali Manoj

Aims: We aim to demonstrate why deeming diffusible reactive oxygen species (DROS) as toxic wastes does not afford a comprehensive understanding of cytochrome P450 mediated microsomal xenobiotic metabolism (mXM). Background: Current pharmacokinetic investigations consider reactive oxygen species formed in microsomal reactions as toxic waste products, whereas our works (Manoj et al., 2016) showed that DROS are the reaction mainstay in cytochrome P450 mediated metabolism and that they play significant roles in explaining several unexplained physiologies (Parashar et al., 2018). Objective: : Herein, we strive detail the thermodynamic and kinetic foundations of murburn precepts of cytochrome P450 mediated drug metabolism. Methodology: Primarily, in silico approaches (using pdb crystal structure files), murburn reaction chemistry logic and thermodynamic calculations to elucidate the new model of CYP-mediated drug metabolism. The theoretical foundations are used to explain experimental observations. Results: We visually elucidate how murburn model better explains- (i) promiscuity of the unique P450-reductase; (ii) prolific activity and inhibitions of CYP3A4; (iii) structure-function correlations of important key CYP2 family isozymes- 2C9, 2D6 and 2E1; and (iv) mutation studies and mechanism-based inactivation of CYPs. Several other miscellaneous aspects of CYP reaction chemistry are also addressed. Conclusion: In the light of our findings that DROS are crucial for explaining reaction outcomes in mXM, approaches for understanding drug-drug interactions and methodologies for lead drug candidates' optimizations should be revisited.


2018 ◽  
Vol 17 (1) ◽  
pp. 6-13 ◽  
Author(s):  
T. V. Osipova ◽  
V. M. Bukhman

The development of new medicines is one of the priority areas of translational medicine. A significant role for biomarkers (BM) that assess the safety and efficacy of new drugs. The right choice of BM reduces the time and costs necessary for the development of drugs and transfer them to the clinic. The review is devoted to the analysis of modern scientific literature on the role of previously known and newly discovered BM in translational research. Translational BM (TBM) established during preclinical studies and are applicable at all stages of the study. TBM should have a high sensitivity and specificity, be easily measured in real time in an easily accessible biological fluids, to evaluate the same process in different species of animals (including humans), make it possible to compare the results of clinical trials with preclinical. The main role of the TBM toxicity to predict, identify and monitor the toxicity of drugs at all stages of their study. The international consortium (Predictive Safety Testing Consortium, PSTC) whose main task is the qualification of new TBM toxicity and the search for new, more advanced than existing methods for testing markers, was established. Under PSTC formed 6 working groups, each of which coordinates research for the study and selection of TBM toxicity caused by the administration of drugs in the liver, kidney, heart and blood vessels, skeletal muscle, testes. The first qualified consortium markers were 7 contained in the urine markers for preclinical studies on rats with the goal of establishing early lesions in the kidney induced by drugs. Only a small number of BM used in the study of new drugs, can be translational.


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