Absorption, distribution, metabolism spectrometry

From a DMPK perspective, a common goal is to be able to compare multiple compounds based on their absorption, distribution, metabolism and excretion (ADME) properties as well their preclinical PK properties [8, 12-22]. Therefore, lead optimization typically is performed as an iterative process that uses the DMPK data to select structural modifications that are then tested to see whether the DMPK properties of the series have been improved. This iterative process is shown schematically in Fig. 13.2. Clearly an important element for the successful lead optimization of a series of NCEs is the ability to perform the DMPK assays in a higher throughput manner. The focus of this chapter will be to discuss ways that mass spectrometry (MS), particularly HPLC-MS/MS can be used to support the early PK studies for NCEs in a higher throughput manner. 

With the success of combinatorial chemistry and HTS. more and more new structural entities are created or acquired and lead compounds discovered. As a consequence, there is an increased demand for high throughput measurement of the quality, physiochemical, and pharmaceutical properties of absorption, distribution, metabolism, and excretion (ADME) of these compounds. This increased demand has created opportunities for the application of mass spectrometry to these research activities. 

Part V targets applications that are organized according to specific compound classes of analytes. The role of mass spectrometry in peptide and protein characterization and in proteomics is the subject of Chapter 18. Next, the topic of carbohydrate analysis by ESI and MALDI is tackled in Chapter 19. This is followed by an examination of ESI and MALDI applications to lipid analysis (Chapter 20). Finally, the important subject of drug discovery is addressed in Chapter 21, including in vitro ADME (absorption, distribution, metabolism and excretion) profiling and pharmacokinetic screening. 

Similarly, carbon-14-labeled compounds have no equal for assessment of their metabo-hsm in vitro (such as with hepatocytes, cytochrome P450 subtypes or other enzyme or subceUular tissue preparations), or for in vivo characterization of their absorption, distribution, metabolism and excretion (ADME) in animals and humans, as they can be detected by several different methods and accurately quantified in complex biological matrices. One of the newer of these methods is accelerator mass spectrometry (AMS)", whose exquisite sensitivity allows the use of far smaller quantities of carbon-14 than standard ADME studies, therefore providing increased safety margins with regard to radiation exposure to human volunteers. 

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