Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of xenobiotics. Xenobiotics are substances that are foreign to the body and include natural or synthetic chemicals, drugs, pesticides, environmental agents, and industrial agents.49 Mathematical models and equations are used to describe and to predict these phenomena. Pharmacodynamics is the term used to describe an investigation of the relationship of xenobiotic concentration to clinical effects. Toxicokinetics, which is analogous to pharmacokinetics, is the study of the absorption, distribution, metabolism, and excretion of a xenobiotic under circumstances that produce toxicity. Toxicodynamics, which is analogous to pharmacodynamics, is the study of the relationship of toxic concentrations of xenobiotics to clinical effect.
Overdoses provide many challenges to the mathematical precision of toxicokinetics and toxicodynamics because many of the variables, such as dose, time of ingestion, and presence of vomiting, that affect the result are often unknown. In contrast to the therapeutic setting, atypical solubility characteristics are noted, and saturation of enzymatic processes occurs. Intestinal or hepatic enzymatic saturation or alterations in transporters may lead to enhanced absorption through a decrease in first-pass effect. Metabolism before the xenobiotic reaches the blood is referred to as the first-pass effect.2,76 Saturation of plasma protein binding results in more free xenobiotic available in the serum, plasma, and blood. Saturation of hepatic enzymes or active renal tubular secretion leads to prolonged elimination. In addition, age, obesity, gender, genetics, chronopharmacokinetics (diurnal variations), and the effects of illness and compromised organ perfusion all further inhibit attempts to achieve precise analyses.3,17,40,45,68,72 In addition, various treatments may alter one or more pharmacokinetic and toxicokinetic parameters. There are numerous approaches to recognizing these variables, such as obtaining historical information from the patient's family and friends, performing pill counts, procuring sequential serum concentrations during the phases of toxicity, and occasionally repeating a pharmacokinetic evaluation during therapeutic dosing of that same agent to obtain comparative data.
Despite all of the confounding and individual variability, toxicokinetic principles may nonetheless be applied to facilitate our understanding and to make certain predictions. These principles may be used to help evaluate whether a certain antidote or extracorporeal removal method is appropriate for use, when the serum concentration might be expected to decrease into the therapeutic range (if one exists), what ingested dose might be considered potentially toxic, what the onset and duration of toxicity might be, and what the importance is of a serum concentration. While considering all of these factors, the clinical status of the patient is paramount, and mathematical formulas and equations can never substitute for evaluating the patient. This chapter explains the principles and presents the mathematics in a user-friendly fashion.79 The application of these principles and mathematical approaches by example and case illustration are found on the website.
Absorption is the process by which a xenobiotic enters the body. A xenobiotic must reach the bloodstream and then be distributed ...