Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy.

The purpose of this paper is to document the procedures needed to construct pharmacokinetic models based on physiologic, physicochemical, and pharmacologic principles. Extensive descriptions of the basic ideas are provided, along with the corresponding equations. The notions of scaling between various animal species will be described and examples will be given. The important factors determining the choice and number of compartments are based on the properties of the drug and the desired purposes of the pharmacokinetic model. The important concept of flow-limiting conditions with regard to local uptake will be described. The quantitative description of plasma and tissue binding is discussed, along with the notion of effective protein concentrations for the latter. Using these basic ideas, the fundamental mass balances describing the flow, diffusion, and reactions of the drug are presented. An example of the prediction of the pharmacokinetics of a strongly bound drug is used as an illustration of the methods, and this example also indicates the types of useful simplifications that can be made. The special, but important, case of linear binding is next derived, and an example involving the drug methotrexate will illustrate the principles involved. Finally, cytosine arabinoside will be used to indicate methods that can be used for rapidly metabolized drugs. Since existing examples are primarily utilized, this paper brings together a comprehensive collection of the several sets of physiologic data and modeling techniques that have been used for the past several years. It is hoped that this documentation will provide a useful basis for the those wishing to use this approach to pharmacokinetics.