Fig. 1

Anatomical and functional differences between the CNS, PNS, and SM (non-NS) barriers, with an overview of key PK parameters for the evaluation of unbound drug exposure. A Morphological structures of neurovascular and muscle microvascular units at the different biological barriers. The structure of the BNB is similar to that of the BBB and BSCB, except that it lacks astrocytes. Compared to the BNB, the neuron-rich region in the BDB lacks pericyte coverage and is leakier. The BSMI structure is similar to that of the BNB, except for the pronounced vesicular transport in endothelial cells. B Expression of influx and efflux membrane transporters on the endothelial and parenchymal cellular barriers. For the illustration purposes, only representative transporters are indicated on the luminal side of the endothelial cells (not necessarily their actual location). Further, only representative influx and efflux transporters are shown at the cellular membrane since the expression of specific transporters is often not reported. The passive diffusion is indicated by two parallel arrows pointing in opposite directions. C The extent of unbound drug transport across the biological barriers is characterized by the unbound tissue extracellular-to-plasma concentration ratio (K_p,uu) and unbound tissue intracellular-to-extracellular concentration ratio (K_p,uu,cell)