ABSTRACT
The outcome of exposure to xenobiotics, whether it is as regimented as multiple dosing kinetics of therapeutic agents following the PK/TK models (Chapters 10 through 12), or as unsystematic as random exposure to environmental pollutants following the stochastic models, is the accumulation of the compounds in the body. In the case of regimented exposure, the purpose is to achieve a consistent pharmacological response for a period of time longer than duration of action of a single dose (Krüger-Thiemer, 1966, 1969; Krüger-Thiemer and Bünger, 1965). Similar to uninterrupted zero-order input (Chapter 11), which resulted in the accumulation of the infused compound in the body, multiple dosing administration also accumulates the compound in the body following the administration of a xed dose and dosing interval (Van Rossum and Tomey, 1968). Unlike the continuous infusion, however, the plasma concentration of administered compound uctuates after each dose reaches a maximum concentration, or peak level, and then declines to a minimum concentration or trough level (Wagner et al., 1965; Gibaldi and Perrier, 1982). In this type of regimented exposure, the dose is usually kept constant and a dosing interval (τ) is selected as a xed interval approximately equal to the half-life of the compound. This means that during each dosing interval approximately 50% of amount in the body eliminates and 50% remains in the body. Thus, peak and trough levels of each dose will be higher than previous doses. Since the dose and dosing interval are kept constant, after a nite time the administered dose will become equal to the amount eliminated from the body. This is when the steady-state uctuations (i.e., peak and trough) are achieved and the amount accumulated in the body is at its anticipated maximum level of the designed dosing regimen (Buell et al., 1969; Wagner, 1975; Gibaldi, 1982). A well-designed dosing regimen for therapeutic agents maintains the uctuation at steady state within the therapeutic range (Levy, 1974). The concept of attaining and maintaining the steady state is similar to intravenous infusion, which is the rate of input equal to the rate of output. In a multiple dosing steady state, the xed administered dose is equal to the amount eliminated from the body in a dosing interval. The xed dose that is given on a regular basis in a xed dosing interval is known as the maintenance dose.
