Application of Quantitative NMR in Pharmacological Evaluation of Biologically Generated Metabolites: Implications in Drug Discovery
| Autor: | Rasmy Talaat, JoAnn Scatina, Abdul E. Mutlib, Robert Espina, Zecheng Chen, Inder Chaudhary, Tarek S. Mansour, Aranapakam Mudumbai Venkatesan, Christoph Martin Dehnhardt, Kathlene Babalola, Karthick Vishwanathan |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Drug Magnetic Resonance Spectroscopy media_common.quotation_subject Metabolite Drug Evaluation Preclinical Pharmaceutical Science Biology Pharmacology Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Pharmacometabolomics Animals Humans Structure–activity relationship Active metabolite media_common Drug discovery Stereoisomerism Biological activity Magnetic Resonance Imaging Rats Macaca fascicularis Pharmaceutical Preparations Drug development chemistry Microsomes Liver |
| Zdroj: | Drug Metabolism and Disposition. 39:106-116 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.110.032490 |
| Popis: | It is important to gain an understanding of the pharmacological activities of metabolite(s) of compounds in development, especially if they are found in systemic circulation in humans. Pharmacological evaluation of metabolites is normally conducted with synthetic standards, which become available during various stages of drug development. However, the synthesis of metabolite standards may be protracted, taking anywhere from several weeks to months to be completed. This often slows down early pharmacological evaluation of metabolites. Once a metabolite(s) is found to possess comparable (or greater) pharmacological activity than the parent compound, additional studies are performed to better understand the implications of circulating pharmacologically active metabolite(s). To conduct some of these studies as early as possible without slowing the progression of a compound in development is important, especially if critical go or no-go decisions impinge on the outcomes from these studies. Early pharmacological evaluation of significant metabolites is hereby proposed to be conducted in the drug discovery stage so that all pertinent studies and information can be gathered in a timely manner for decision-making. It is suggested that these major metabolites be isolated, either from biological or chemical sources, and quantified appropriately. For biologically generated metabolites, NMR is proposed as the tool of choice to quantitate these metabolites before their evaluation in pharmacological assays. For metabolites that have the same UV characteristics as the parent compound, quantitation can be conducted using UV spectroscopy instead of NMR. In this article, we propose a strategy that could be used to determine the pharmacological activities of metabolites isolated in submilligram quantities. |
| Databáze: | OpenAIRE |
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