Absorption-distribution-metabolism-excretion ADME studies

Absorption, distribution, metabolism, excretion (ADME) studies... 

For radiolabeled proteins,placement of the radiolabel is critical to the success of the study in regards to tissue distribution and other parameters related to absorption-distribution-metabolism-excretion or ADME characterization. 

An oral ADME (absorption, distribution, metabolism, excretion, following oral administration of the pesticide) study may also be of utility in refining the risk assessment. If a default value for dermal absorption of 100 % is applicable based on the physico-chemical properties of a substance and an appropriate oral ADME study is available, the results of this study may be used to refine the default value for dermal absorption. It is required that the oral absorption is determined at low dose levels in experimental animals, in order to obtain an accurate estimate of the oral absorption. Based on theoretical grounds and supported by a comparison of oral and dermal absorption data available for twelve pesticides, it is assumed that dermal absorption will not exceed oral absorption (Hakkert et al unpublished data). 

The physicochemical properties of compounds are extremely important in pharmaceutical and environmental studies. These properties determine the behavior of organic molecules in the environment as well as their biological and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties as drugs. 

The sensitivity and selectivity brought to drug discovery by the routine use of HPLC/MS/MS has revolutionized biopharmaceutical capabilities. This impact has been realized in the form of increased throughput and decreased cycle time. In a highly significant sense, these new analytical methods have enabled the introduction of absorption distribution metabolism excretion studies much earlier in discovery than previously possible. At one time the investment of lengthy assay development for transport studies on a discovery candidate was nearly unthinkable. With HPLC/MS/MS, this barrier has been removed. Prime ADME information can be provided at the earliest stages of discovery to aid in the selection of lead candidates. 

If the main objective is the discovery of new drug candidates, medicinal chemistry is also concerned with the fate of drugs in living organisms ( ADME studies absorption, distribution, metabolism, excretion), and with the study of bioactive compoimds not related to medicine (agrochemicals, food additives, etc.). 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

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. 

For a drug to interact with a target, it has to be present in sufficient concentration in the fluid medium surrounding the cells with receptors. Pharmacokinetics (PK) is the study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs. It analyzes the way the human body deals with a drug after it has been administered, and the transportation of the drug to the specihc site for drug-receptor interaction. For example, a person has a headache and takes an aspirin to abate the pain. How does the aspirin travel from our mouth to reach the site in the brain where the headache is and act to reduce the pain ... 

Pharmacodynamics (PD) is the study of interactions between drugs and the body while pharmacokinetics (PK) describes the absorption, distribution, metabolism, and excretion (ADME) of drugs by the body. 

To Study interactions between proteins and drugs, an available tool is the Drug Absorption, Distribution, Metabolism, and Excretion (ADME) Associated Protein Database (see Table 1.5). The database contains information about relevant proteins, functions, similarities, substrates and hgands, tissue distributions, and other features of targets. Eor the understanding of pharmacokinetic (PK) and pharmacodynamic (PD) features, some available resources are listed in Table 1.5. For example, the Pharmacokinetic and Pharmacodynamic Resources site provides links to relevant software, courses, textbooks, and journals (see Note 5). For quantitative structure-activity relationship (QSAR), the QSAR Datasets site collects data sets that are available in a structural format (see Table 1.5). 

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. 

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