Pharmacokinetics metabolism, elimination processes

The drug discovery and development processes are time consuming and costly endeavors. It has been reported that on average it takes 10 to 15 years and costs more than 800 million to bring a molecule from discovery to market.12 Compounds fail for various reasons. One that accounts for a reported 40% of failures in clinical trials is poor pharmacokinetics.3 In an effort to improve the number of compounds that exhibit optimal absorption, distribution, metabolism, elimination (ADME), and pharmacokinetic (PK) properties and reach development, drug metabolism and pharmacokinetic scientists continually implement new technologies and compound screening approaches. 

A key consideration regarding the practical aspects of biomarkers is the pharmacokinetics of the chemical. The measure usually referred to is the half-life, which reflects both the affinity of the chemical for the biologic matrix and the efficiency of metabolic or elimination processes. Knowledge of half-life is important for several reasons, including its use in determining sampling time (Bernard 1995). For instance, chemicals with short half-lives (a few days or even a few hours)—including cotinine, phthalates, volatile... 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

The scope of mechanisms causing pharmacokinetic interactions may include alterations in one or more of the absorption, distribution, metabolism, and elimination processes. The alterations may reflect effects of the developmental drug on the pharmacokinetics of the potential interaction partner, and vice versa. 

Conceptual models of percutaneous absorption which are rigidly adherent to general solutions of Pick s equation are not always applicable to in vivo conditions, primarily because such models may not always be physiologically relevant. Linear kinetic models describing percutaneous absorption in terms of mathematical compartments that have approximate physical or anatomical correlates have been proposed. In these models, the various relevant events, including cutaneous metabolism, considered to be important in the overall process of skin absorption are characterized by first-order rate constants. The rate constants associated with diffusional events in the skin are assumed to be proportional to mass transfer parameters. Constants associated with the systemic distribution and elimination processes are estimated from pharmacokinetic parameters derived from plasma concentration-time profiles obtained following intravenous administration of the penetrant. 

Two distinct bases for these types of effects may be distinguished pharmacokinetic and pharmacodynamic. Pharmacokinetic-based toxic effects are due to an increase in the concentration of the compound or active metabolite at the target site. This may be due to an increase in the dose, altered metabolism or saturation of elimination processes for example. An example is the increased hypotensive effect of debrisoquine in poor metabolizers where there is a genetic basis for a reduction in metabolic clearance of the drug (see Chapter 5). 

The pharmacokinetic parameters-elimination half life, elimination rate constant, the apparent volume of distribution and the systemic, renal and metabolic clearances (Cls, Clr, and Clm, respectively) for a dmg are always independent of the dose administered as long as the drug follows a first-order elimination process and passive diffusion. 

This generally describes the process of drug absorption into the body, distribution throughout the body, metabolism by degrad a tive and metabolizing enzymes in the body, and finally elimination from the body. It is useful to consider each of these steps because together they summarize pharmacokinetics. 

During the past decade, numerous articles reviewing the effects of aging on pharmacokinetic processes (i.e., absorption, distribution, metabolism, and elimination) have been published [115 124h]. An outline of the observations made in these reports is supplied in Table 5. The absorption process is the only process that will be covered in depth in this chapter, as this is the process that can most easily be manipulated through formulation techniques. 

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. 

The most important processes assessed in pharmacokinetic studies are absorption (uptake of a drug from the digestive tract), distribution (compart-mentalization in the body), metabolism (conversion or breakdown, especially in the liver) and elimination (excretion), summarized by the abbreviation ADME. 

Pharmacokinetics What the body does to the drug. The process of drug absorption from the site of administration, distribution to the target organ and other bodily compartments, metabolism or biotransformation (if necessary), and eventual elimination. 

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