Pharmacokinetic studies, drug discovery

Chen, Y. et al., High throughput strategies for metabolite identification in drug discovery pharmacokinetic studies, Proceeding of 56st ASMS Conference on Mass Spectrometry and Allied Topics. Denver, CO, June 1-5, 2008. 

Robust and rugged LC-MS/MS methods are essential in support of drug discovery, toxicology studies, and clinical trials, for the data generated from these bioanalytical methods is used to evaluate the bioavailability, bioequivalence, toxicokinetic, and pharmacokinetic parameters of drug candidates. Thus, it is critical to invest significant thought and effort in the method development process [25-27], Fast sample... 

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Metabolic stability in human liver preparations may represent a suitable experimental tool to obtain relevant pharmacokinetic information in an early phase of drug discovery. Compounds which are metabolized principally by the liver can be identified and studied in more detail to determine the principal sites of biotransformation. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

Automated online SPE systems have been applied to various phases of drug discovery. McLoughlin et al. (1997) utilized the Prospekt system in pharmacokinetic animal studies for rapid drug candidate screening. Up to 10 compounds were simultaneously monitored. The lower limits of detection were... 

The present revised textbook on Pharmaceutical Drug Analysis caters for the much needed handbook and reference book, which is absolutely current with regard to the esteemed philosophy of analytical chemistry, an obvious solid support towards drug discovery, development, stability studies, bioavailability and pharmacokinetic studies, and above all the quality assurance of pure drugs together with their respective dosage forms. 

For a number of years following the discovery and initial clinical use of vinblastine and vincristine, there was relatively little definitive information about the pharmacokinetics of these compounds. Pharmacokinetic studies were accomplished typically using radiolabeled drugs and procedures that were of limited value in distinguishing parent drugs from putative metabolites. 

QSAR and neural network approaches in combination with physiologicaUy-based pharmacokinetic (PBPK) modelling hold promise in becoming a powerful tool in drug discovery [45]. Below we briefly discuss some of these studies. 

Having access to metabolism data in the early discovery stage is invaluable. For example, hepatic metabolism data could be used to characterize the pharmacokinetic behavior of a perspective lead. Several studies have reported how metabolism databases and software systems have been used at various settings (272). In this section, we will provide an overview of recent databases, software systems, websites, tools, and services that could be potential starting points for metabolism modeling at various stages in drug discovery process (271,273). 

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