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CHAPTER OBJECTIVES

  • Define the pharmacokinetic terms used in a two- and three-compartment model.

  • Explain using examples why drugs follow one-compartment, two-compartment, or three-compartment kinetics.

  • Use equations and graph to simulate plasma drug concentration at various time periods after an IV bolus injection of a drug that follows the pharmacokinetics of a two- and three-compartment model drug.

  • Relate the relevance of the magnitude of the volume of distribution and clearance of various drugs to underlying processes in the body.

  • Explain the consequences of using Vc, Varea (or Vβ), versus Vss to calculate a loading dose

  • Estimate two-compartment model parameters by using the method of residuals.

  • Calculate clearance and alpha and beta half-lives of a two-compartment model drug.

  • Explain how drug metabolic enzymes, transporters, and binding proteins in the body may modify the distribution and/or elimination phase of a drug after IV bolus.

INTRODUCTION

Pharmacokinetic models are used to simplify all the complex processes that occur during drug administration, including 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 1, pharmacokinetic models are used to simulate drug disposition under different conditions/time points so that optimal dosing regimens for individuals or groups of patients can be designed.

Compartmental models are classic pharmacokinetic models that simulate the kinetic processes of drug absorption, distribution, and elimination with minimal physiologic details. In contrast, the more sophisticated physiologic models are discussed in Chapter 19. In compartmental models, drug concentrations are assumed to be uniform and instantly distributed within each given hypothetical compartments. Hence, all muscle mass and connective tissues may be lumped into one hypothetical tissue compartment that equilibrates with drug from the central (composed of blood, extracellular fluid, and highly perfused organs/tissues such as heart, liver, and kidneys) compartment. Conventionally, 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 (or more commonly referred to as the peripheral compartment as Cp) can be calculated. Obviously, in contrast to compartment models, the drug concentrations in a particular tissue mass may not be homogeneously distributed. In reality, the body is more complex than depicted in the simple one- and multicompartment models, and the eliminating organs, such as the liver and kidneys, are much more complex than being simple extractors. Multicompartment models are helpful to gain a better appreciation regarding how drugs are handled in the body. Contrary to the monoexponential decay observed with the simple one-compartment model, most drugs given by IV bolus dose decline in a biphasic fashion; that is, plasma drug concentrations rapidly decline soon ...

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