Absorption, distribution, metabolism and excretion ADME

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. 

It is important to understand the need for the multiple assays that are now routinely performed by most pharmaceutical companies to measure various absorption distribution metabolism and excretion (ADME) parameters to determine the pharmacokinetic (PK) properties of new chemical entities (NCEs). The goal of new drug discovery is to find NCEs that have the appropriate... 

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. 

Pharmacokinetics and metabolism - absorption, distribution, metabolism and excretion (ADME), including potential for interactions, polymorphisms of drug metabolising enzymes and exposures in man predicted from interspecies allometric scaling... 

The physical properties and pharmacokinetic profile, with data on absorption, distribution, metabolism and excretion (ADME) in animals, form an essential part of the drug selection process since the desired pharmacokinetic profile... 

Absorption, distribution, metabolism and excretion (ADME) of the test substance after oral administration in one species, usually the rat, as well as dermal absorption in vitro (human and rat skin) or in vivo (rat)... 

James, M., Moore, M., Plotzke, K., Segner, H., Schultz, I., Thomas, K., Vasiluk, L. and Weisbrod, A. (2007) Use of in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) data in bioaccumulation assessments for fish. Human Ecol Risk Assess, 13, 1164-1191. 

The plasma level of a toxic compound is a particularly important parameter, as (i) it reflects and is affected by the absorption, distribution, metabolism, and excretion (ADME) of the compound (fi) it often reflects the concentration of compound at the target site more closely than the dose it should be noted that this may not always be the case such as when sequestration in a particular tissue occurs which may or may not be the target tissue, for example, chlorphentermine (see Fig. 3.19), lead and, polybrominated biphenyls (Fig. 3.20) ... 

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

During preclinical development, the structure, physical and chemical characteristics, and stereochemical identity of the IND/CTA candidate are fully characterized. This information, for example, is required for the chemical manufacture and control (CMC) section of the IND. Appropriate bioanalytical methods are developed for the evaluation of pharmacokinetics, typically a series of studies focusing on absorption, distribution, metabolism, and excretion (ADME) in toxicology species, as well as systemic exposure and metabolism in toxicological and clinical studies. 

As was noted in Chapter 4, pharmacokinetic and pharmacodynamic effects are studied in nonclinical research. These topics are also of critical importance in clinical investigations. A drug s pharmacokinetics and pharmacodynamics are of considerable interest to clinicians who may prescribe the drug to patients once it is approved. Meaningful decisions about a drug s optimal use can only be made with an understanding of the time course of events that occur after the drug s administration, and both pharmacokinetics and pharmacodynamics are concerned with this time course. By consideration of the pharmacokinetic processes of absorption, distribution, metabolism, and excretion (ADME), the... 

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