The PK-Sim® standard distribution model assumes 4 subcompartments per organ, i.e. compartments for blood cells, plasma, interstitial space, and cellular space. This model type considers a permeation barrier between plasma and interstitial space and takes into account that the interstitial space has a lower protein content than the plasma. It is especially suitable for small molecules.
The plasma-interstitial partition coefficients result from the lower protein concentration in the interstitial space compared to plasma and the unbound fraction in plasma. It is assumed, that the drug has the same affinity to plasma as to interstitial proteins. Thus, effects from the partitioning between plasma and interstitial space may (depending on other physico- chemical data) become important for compounds with a low fraction unbound.
The rate of permeation through the endothelial barrier between plasma and interstitial space is determined by the product of endothelial permeability and surface area. The drug dependent permeability can be defined within the Distribution Tab and the individual dependent surface area can be defined for the individual. In the present version of PK-Sim®, the endothelial permeability parameters of the plasma-interstitial barriers are not calculated from physico-chemical compound data. The default value for the plasma-interstitial permeabilities is very large, i.e. the permeabilities have to be adjusted manually, if the permeation across the plasma-interstitial barriers of the organs is expected to be restricted. Using the large default value for plasma-interstitial permeabilities, the exchange rate between plasma and interstitial in 4 subcompartments model are almost instantaneous.