Pharmacokinetics in organs and the intact body: model validation and reduction.

Physiological pharmacokinetic models are based on the structure of the circulatory system reflecting the convective transport of drug by blood flow to the various organs and tissues. Distribution kinetics at the organ level is mostly simplified as transfer between well-stirred compartments neglecting a priori the effects of intravascular dispersion and diffusion within tissue parenchyma. Recirculatory models based on residence time theory overcome these structural limitations since they allow in a most general way the decomposition of the body into its natural subsystems. Because of the unidentifiability of the global multi-organ model on the basis of plasma concentration-time curves the following methods/experimental designs will be discussed which provide quantitative information regarding the subsystems under in vivo conditions: (i) determination of tissue concentration-time profiles (destructive sampling), (ii) estimation of the organ transit time density from input/output profiles and (iii) application of a recirculatory model with reduced complexity to clinical pharmacokinetic data.