Brain distribution of acetaminophen in the rat. a) Data obtained for acetaminophen in the rat following an intravenous dose of 15 mg/kg, administered by constant-rate infusion for 10 minutes. The data are presented as the average (geometric mean ± SEM) of the observed unbound acetaminophen concentration-time profiles in plasma (black, n = 10), striatum ECF (ST, blue, n = 10), CSF in lateral ventricle (LV, green, n = 14), and CSF in cisterna magna (CM, red, n = 8). The data show that brain ECF (striatum) concentrations are comparable to those in plasma and significantly higher than those in both the lateral ventricle and the cisterna magna CSF compartments. b) The physiologically-based pharmacokinetic model for the rat developed on the basis of the data obtained for acetaminophen as shown in a). This model describes the obtained data adequately, and predicts the CSF acetaminophen concentrations in the third and fourth ventricle (lumped as TFV) as well as in the subarachnoid space (SAS), the latter being most representative of the lumbar CSF concentrations . Denotations: In the model clearance (CL, volume/time), and ECF bulk or CSF flow (Q, volume/time) are indicated. Numbering indicates exchange between different compartments: 12 from plasma to peripheral compartment; 21 from peripheral to plasma compartment; 13 from plasma to brain ECF compartment; 31 from brain ECF to plasma compartment; 14 from plasma to CSFLV compartment; 41 from CSFLV to plasma compartment; 15 from plasma to CSFTFV compartment; 51 from CSFTFV to plasma compartment; 16 from plasma to CSFCM compartment; and 61 from CSFCM to plasma compartment.