A four-compartment model was derived to analyze drug exchange among cerebral capillary plasma, cerebrospinal fluid (CSF), and the brain extracellular and intracellular (or bound) compartments. Equations that were derived incorporated the factor of cerebral blood flow. They were fit by nonlinear least squares to measured brain, plasma, and CSF (when available) concentrations of [14C]urea in the rat, in response to a step increase in plasma concentration, to intravenous infusion, or to a bolus injection of tracer. Best-fit values for the transfer constants were consistent among the three administrative regimens and agreed with published values, when available. Expressions also were derived and numerically evaluated for the lower limit of the brain extracellular space, for half times of brain [14C]urea uptake, and for the steady-state brain/plasma distribution volume. The model should make it possible to use transfer constants obtained for a given drug from one study (e.g., constant plasma concentration) to predict brain concentrations from measured plasma concentrations in other acute or chronic studies.