ABSTRACT
The goals of drug metabolism and pharmacokinetics (PK) as they apply to toxicology in general and pathology in particular are simple; place the biological observations (toxicity, tissue damage, species differences) in a chemical, physiological, and quantitative context. While many of the drug development and regulatory conclusions are still based on dosage (e.g., NOAEL), it is the concentration of parent or metabolite at the site of toxicity (or its surrogate, plasma or serum) and the time course of drug appearance and elimination that provide a scientically rigorous interpretation of the observations and enable the formation of hypotheses. The objectives of this chapter are to provide the reader with a working understanding of the critical toxicokinetic (TK) parameters, how they are derived and applied, and what they mean. While distinctions have been drawn between the use of “toxicokinetics” or TK and “pharmacokinetics” or PK, the concepts and mathematics underlying the parameters used to describe the time course of a molecule’s fate in a biological system are the same, whether the molecule is a toxin or a potential therapeutic. This chapter will refer to TK parameters as those calculated for a molecule or metabolite after high dosages in a toxicology study, ignoring the characterization of the molecule’s biological activity. In practice, most of these data are presented and discussed in a team setting; therefore, understanding the design, limitations, and
3.1 Introduction and Objective ..................................................................................................... 55 3.2 Importance of Exposure-Based Interpretation .......................................................................56 3.3 TK or PK Parameters: What They Are, How They Are Derived, and What They Mean ..... 57
3.3.1 Plasma Concentration-Time Curves: Where the Numbers Come From .................... 58 3.3.2 TK Parameters Derived from Raw Data ....................................................................60 3.3.3 TK Parameters Derived from Transformed Data .......................................................60
