Question : Give a basic introduction on PHYSIOLOGICAL PHARMACOKINETICS?

Answer: The history and bases of physiological pharmacokinetics will be briefly reviewed, pointing out some misconceptions, e.g. that membrane transport cannot be incorporated into these models and only the flow-limited case can be handled. Several recent literature reviews will be given for those wanting further details on the modeling and/or specific drugs. This will be followed by a brief description of a few examples, and the paper will conclude with my views of the most useful future research in the area.

The basic idea of physiological pharmacokinetics was to extend pharmacokinetic modeling so that quantitative aspects of other biological areas can be incorporated. For example, this includes what is known about physiological differences and similarities between species, membrane biophysics, biochemical kinetics, and others to be illustrated later. The approach will be to focus the models on anatomically real local tissue regions, including their blood flow, binding and transport characteristics. Certain aspects are similar to the compartmental modeling methods of mathematical biology, see, e.g. Riggs (1970) or Resigno and Segre (1966)---or of what will be termed "classical pharmacokinetics' which is primarily concerned with the prediction of blood levels for various dosage regimens--see Gibaldi and Perrier (1982) for a comprehensive treatment.

Often, however, these compartments have been rather abstract mathematical constructs, whose number and properties were only able to be ascertained by curve-fitting of experimental blood sample data. Useful insights into the quantitative operation of the body were obtained, although specific organ levels were usually not considered. However, physiological pharmacokinetics attempts to also predict the various organ and tissue levels, even extra- vs intra-cellular concentrations.

This concept of utilization of known anatomical and physiological functions as a basis for pharmacokinetic models was earlier proposed by Teorell (1937). This remarkable work was not able to be fully utilized, however, because of the lack of reasonable computing capabilities. When the latter became feasible, the number of differential equations that needed to be solved in comprehensive models was not of crucial importance, and multicompartment models based on known physiology were formulated by Bischoff and Brown (1966). The basis was to use a compartment as an actual local tissue region, as proposed by Bellman et al. (1960).

There are several specific reasons for pursuing this approach. One is the scientific intellectual satisfaction of having quantitative predictive models based on underlying knowledge, rather than the more empirical, curvefitting approaches often used. The latter are always needed to some extent, of course, but should hopefully be minimized. Another important purpose is to aid in the constant problems of interpreting animal experiments in drug screening, dosage regimen formulation, and similar matters. In quantitative terms this can be called 'scaling' the results from one species to another, and ultimately to man, as described by Dedrick (1973).

Both of these results should ultimately result in more efficient experimentation, since the aspects that can be predicted a priori can be done by model, allowing the investigator to focus more specifically on the truly unknown areas. A feature that has both research and practical importance is that the model results are mostly concerned with organ concentrations of drug; this appears to be of increasing interest both for clinical application and also will provide a much clearer basis for studying pharmacodynamics (drug effects) for agents with known sites of action.

The philosophical basis of the present approach resides in chemical engineering modeling and design, where several of the problems of combined flow, diffusion, and chemical reactions are similar to the present problem--see Himmelblau and Bischoff (1968).