Brown, RP; Delp, MD; Lindstedt, SL; Rhomberg, LR; Beliles, RP
Physiologically based pharmacokinetic (PBPK) models are being used increasingly by regulatory agencies to estimate the internal dose of toxic agents or their metabolites to target tissues. Using this technique, risk assessments for toxic substances can be based on estimates of the amount of the agent that reaches the target tissue, rather than on the applied dose. In PBPK modeling, the pharmacokinetic behavior of a compound in the body-that is, its absorption, distribution, metabolism, and elimination-is represented by equations that attempt to quantitatively describe actual physiological processes. The parameters of these equations are key anatomical and physiological descriptors of the organism, such as organ volume, organ perfusion rates, and breathing rates. Values for these parameters can be determined experimentally, external to the process of fitting the model to the data. The advantage of such an approach is that a given model structure can be used to describe different species, sexes, strains, and conditions through choice of an appropriate set of parameter values. Although models are invariably simplifications of complex processes, their performance, accuracy, and biological relevance are enhanced by accurate specification of parameter values. Accurate characterization of parameter values is especially important for those parameters that have the greatest effect on the predictive ability of the model.
Absorption/physiology; Adipose Tissue/physiology; Animals; Body Weight/physiology; Cardiac Output; Dogs; Female; Humans; Male; Mice; Models, Biological; Organ Size/physiology; Pharmacokinetics; Rats; Tissue Distribution/physiology