Figure 1.

Model structure of the whole-body PBPK model integrated with a 4-compartment permeability-limited brain (4Brain) model, which has 4 compartments representing the brain blood, brain mass, cranial cerebrospinal fluid (CSF), and spinal CSF. The 4Brain model assumes: 1) drug transport across the BBB is governed by bi-directional passive permeability (PSB) and ABCB1- and ABCG2-mediated active efflux clearance (CL_efflux,BBB); 2) drug transport across the blood-CSF barrier was controlled by bidirectional passive permeability (PSC) and ABCB1-mediated active influx clearance (CL_uptake,CSF); 3) drug transport between the brain mass and cranial CSF is diffusive transport at a bi-directional clearance (PSE); 4) fluid balance is maintained by the circulation of CSF between spinal and cranial compartments and reabsorbed into the brain blood; 5) the cerebral blood flow rate (Q_Brain) links the 4Bain model to whole-body model; 6) only unbound and unionized drug can passively pass through all barriers, while transporters act upon unbound drug (including both unionized and ionized species); 7) metabolism in brain mass is negligible; and 8) all compartments are well-stirred with defined volumes. Flow rates are described by the CSF secretion rate (Q_BCSFB), bulk flow rate from brain mass to cranial CSF (Q_bulk), CSF flow rate out of cranial and spinal compartments (Q_sink), CSF shuttle flow rate between cranial and spinal compartments (Q_Sin and Q_Sout), and water transfer rate from the brain blood to brain mass (Q_BBB).