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  • Toxicokinetics is the study of the modeling and mathematical description of the time course of disposition (absorption, distribution, biotransformation, and excretion) of xenobiotics in the whole organism.

  • The apparent volume of distribution (Vd) is the space into which an amount of chemical is distributed in the body to result in a given plasma concentration.

  • Clearance describes the rate of chemical elimination from the body in terms of volume of fluid containing chemical that is cleared per unit of time.

  • The half-life of elimination (T1/2) is the time required for the blood or plasma chemical concentration to decrease by one half.

Toxicokinetics refers to the quantitative study of absorption, distribution, metabolism, and excretion (ADME) of chemicals in biota through measurement and modeling of their concentrations or amounts in biological matrices (e.g., blood, plasma, excreta, exhaled air, tissues) as a function of time. Experimental studies of toxicokinetics facilitate characterization of the temporal profile of the concentration of chemicals and their metabolites in the target tissue or other biological matrices, reflecting the net effect of the rate and extent of absorption through one or more exposure routes, distribution to tissues and organs via systemic circulation, as well as disposition by metabolism and excretion. Toxicokinetic analyses constitute an essential part of systematic approaches to safety/risk evaluation of xenobiotics and other substances including therapeutic drugs. The models in toxicokinetics range from a simple, one-compartment model to complex multicompartment models, with some explicitly incorporating mechanistic determinants of chemical uptake, distribution, and disposition. This chapter introduces toxicokinetic concepts, fundamentals of classic and physiologic toxicokinetic models, as well as their applications in toxicology, risk assessment, and biomonitoring.


Figure 7–1A presents the blood kinetic data collected in a group of animals as part of the toxicological evaluation of a xenobiotic following a single oral dose of 100 mg/kg body weight. The toxicokinetic curve indicates an initial phase of increasing concentration determined by the rate of absorption, then a peak or plateau during which absorption rate equals elimination rate, followed by a phase dominated essentially by elimination. In this hypothetical example, the mean blood concentration of the parent chemical in the treatment group corresponded to 0, 1.32, 2.74, 3.37, 3.55, 2.89, 1.67, and 0.37 mg/L at pre-exposure, or at 2, 4, 6, 8, 10, 12, and 24 hours post-exposure, respectively. The Cmax,blood is 3.55 mg/L for this treatment group. A common method of calculating the area under the curve (AUCblood) involves summing the areas of trapezoids constituting the time-course curve. The trapezoidal method involves (i) averaging the blood concentrations found at two consecutive sampling times and (ii) multiplying it with the time interval between the two sampling periods (Figs. 7–1B and C). The lower panel illustrates the calculation of AUC for one trapezoid (4.56 (mg/L)·h), using the mean blood concentrations of 2.89 and 1.67 mg/L ...

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