Circulatory models of intact-body kinetics and their relationship with compartmental and non-compartmental analysis

Circulatory models for interpreting the kinetics of substances in vivo explain the kinetics of the intact body with the concepts of organ kinetics. In this paper, it is first shown that classical organ kinetic analysis is incomplete for metabolized substances, and an appropriate extension is developed. It is then discussed how the concepts of the extended organ kinetic analysis apply to circulatory models. At an organ level, it is shown that two impulse responses are necessary to characterize the organ, one relating influx and outflux, and one relating influx and uptake. The consideration of the inlet-uptake path is of fundamental importance for a correct calculation of the organ volume. It is demonstrated that the total volume is the sum of two components, the first related to the inlet-outlet path, the second to the inlet-uptake path. The first term is computable without assumptions, while the second is model-dependent. Analogous results hold at a total-body level. The relationships between circulatory models and compartmental and non-compartmental analysis are also precisely established. The significance of the non-compartmental estimate of the distribution volume is clarified. The usual strategy of compartmental modeling by which losses are placed in peripheral compartments according to a correspondence between tissues and compartments is shown to be misleading. An example concerning glucose kinetics is given. In conclusion, this paper shows that many of the dominating paradigms of organ and total-body kinetic analysis must be revised.