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Pharmacokinetic models are used to simplify all the complex processes that occur during drug administration that include drug distribution and elimination in the body. The model simplification is necessary because of the inability to measure quantitatively all the rate processes in the body, including the lack of access to biological samples from the interior of the body. As described in Chapter 3, pharmacokinetic models are used to simulate drug disposition so dosing regimens for individuals or groups of patients can be calculated.

Compartmental models are classical pharmacokinetic models that simulate the kinetic processes of drug absorption, distribution, and elimination with little physiologic detail. In contrast, the more sophisticated physiologic model is discussed in Chapter 22. In compartmental models, drug tissue concentration, Ct, is assumed to be uniform within a given hypothetical compartment. Hence, all muscle mass and connective tissues may be lumped into one hypothetical tissue compartment that equilibrates with drug from the central (or plasma) compartment. Since no data are collected on the tissue mass, the theoretical tissue concentration cannot be confirmed and used to forecast actual tissue drug levels. Only a theoretical, Ct, concentration of drug in the tissue compartment can be calculated. Moreover, drug concentrations in a particular tissue mass may not be homogeneously distributed. However, plasma concentrations, Cp, are kinetically simulated by considering the presence of a tissue compartment. Indeed, most drugs given by IV bolus dose decline in a biphasic fashion, that is, plasma drug concentrations rapidly decline soon after IV bolus injection, and then decline moderately as some of the drug that initially distributes (equilibrates) into the tissue moves back into the plasma. Although Ct is not useful, Dt, or amount of drug in the tissue compartment is useful because it shows how much drug accumulates extravascularly in the body at any time. The two-compartment model provides a simple way to keep track of the mass balance of the drug in the body.

Multicompartment models provide answers to such questions as: (1) How much of a dose is eliminated? (2) How much drug remains in the plasma compartment? and (3) How much drug accumulates in the tissue compartment? The latter information is particularly useful for drug safety since the amount of drug in a deep tissue compartment may be harder to eliminate by renal excretion or by dialysis after drug overdose.

Multicompartment models explain the observation that, after a rapid IV bolus drug injection, the plasma level–time curve does not decline linearly, implying that the drug does not equilibrate rapidly in the body, as observed for a single first-order rate process in a one-compartment model. Instead, a biphasic or triphasic drug concentration decline is often observed. The initial decline phase represents the drug leaving the plasma compartment (composed of blood and highly perfused tissues) and entering one or more tissue compartments as well as being eliminated. Later, the plasma drug concentrations ...

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