- 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 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. In the classic model, chemicals are said to move throughout the body as if there were one or two compartments that may have no apparent physiologic or anatomical reality. In physiologically based toxicokinetic models, the body is represented as a series of mass balance equations that describe each organ or tissue on the basis of physiologic considerations. There is no inherent contradiction between the classic and physiologically based approaches, yet certain assumptions differ between the two models. Ideally, physiologic models can predict tissue concentrations, whereas classic models cannot.
The least invasive and simplest method to gather information on absorption, distribution, metabolism, and elimination of a compound is by sampling blood or plasma over time. Assuming that the concentration of a compound in blood or plasma is in equilibrium with concentrations in tissues, then changes in plasma toxicant concentrations should reflect changes in tissue toxicant concentrations. Compartmental pharmacokinetic models consist of a central compartment representing plasma and tissues that rapidly equilibrate with chemical, connected to one or more peripheral compartments that represent tissues that more slowly equilibrate with the chemical (Figure 7–1). Chemical is administered into the central compartment and distributes between central and peripheral compartments. Chemical elimination occurs from the central compartment, which is assumed to contain rapidly perfused tissues capable of eliminating the chemical (e.g., kidneys, lungs, and liver). Compartmental pharmacokinetic models require no information on tissue physiology or anatomical structure, and they are valuable in predicting the plasma chemical concentrations at different doses, establishing the time course of chemical in plasma and tissues and the extent of chemical accumulation with multiple doses, and determining effective dose and dose regimens in toxicity studies.
Compartmental pharmacokinetic models wherekais the first-order extravascular absorption rate constant into the central compartment (1),kelis the first-order elimination rate constant from the central compartment (1), andk12andk21are the first-order rate constants for distribution of chemical into and out of the peripheral compartment (2) in a two-compartment model, whereask10is the first-order elimination rate ...