Excretion site, interactions

The effect of any chemical at a biological target depends on its ability to attain a target site concentration that exceeds the threshold required to ehcit the response. The intensity and duration of the response depends on the toxicokinetic properties of the compound (absorption, distribution, metabolism, and excretion) and the nature of the target site interaction (reversible, irreversible). If recovery is complete between successive exposures, no cumulative toxicity is to be expected. However, a short-term acute exposure could potentially add to the long-term burden of a persistent chemical and be relevant for the magnitude of the chronic effect. 

Pharmacokinetic interactions may occur during one or more of the pharmacokinetic processes whereby the drug reaches its site of action and is then eliminated (i.e. absorption, distribution, metabolism and excretion). Such interactions may result in a change in the drug concentration at the site of action with subsequent toxicity or decreased efficacy. 

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

For convenience, the processes identified in Figure 2.1 can be separated into two distinct categories toxicokinetics and toxicodynamics. Toxicokinetics covers uptake, distribution, metabolism, and excretion processes that determine how much of the toxic form of the chemical (parent compound or active metabolite) will reach the site of action. Toxicodynamics is concerned with the interaction with the sites of action, leading to the expression of toxic effects. The interplay of the processes of toxicokinetics and toxicodynamics determines toxicity. The more the toxic form of the chemical that reaches the site of action, and the greater the sensitivity of the site of action to the chemical, the more toxic it will be. In the following text, toxicokinetics and toxicodynamics will be dealt with separately. 

Drug metabolism has been recognized as one of the key factors in the discovery of new chemical entities. A lead compound needs to not only interact with the target enzyme/receptor but also remain over a certain threshold concentration at the site of action for a defined period to produce the desired therapeutic effect. Drug metabolism together with absorption, distribution and excretion are among the factors that influence the final time-concentration relationship of drugs and therefore the potential efficacy of the compound [1],... 

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 ... 

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). 

Pharmacokinetic interactions occur when one drug interferes with the absorption, distribution, metabolism, or excretion of another drug so as to increase or decrease the concentration of free drug in the plasma (and at its site of action). Such interference may be two-way and may involve more than one mechanism. These may augment or counteract each other. 

To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill given orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration. 

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