The unit impulse response theory has been adapted to characterize the transport profile of drugs into the central nervous system (CNS). From the obtained input function, the cumulative plasma volume (V) cleared by transport into the CNS in time can be calculated. Simulation studies demonstrated that transport governed by passive diffusion resulted in a linear relationship between V and time, while the slope of the line, the blood-brain barrier (BBB) clearance, proved to be an adequate and model independent parameter to characterize drug transport into the CNS. The error in the result of the numerical procedure could be limited to less than 10% of the theoretically predicted value. Superposition of 5 or 10% random noise on simulated data did not result in significant differences between the calculated and theoretically predicted clearance values. Simulations of carrier-mediated transport resulted in nonlinear transport curves; the degree of nonlinearity, and thus the detectability, was dependent on the initial degree of saturation of the system, the rate of desaturation, as caused by drug elimination processes and the noise level on the data. In vivo experiments in the rat were performed, using atenolol, acetaminophen, and antipyrine as model drugs. Linear transport relationships were obtained for all drugs, indicating that transport was dependent on passive diffusion or a low affinity carrier system. BBB-clearance values were 7 +/- 1 microliters/min for atenolol, 63 +/- 7 microliters/min for acetaminophen and 316 +/- 25 microliters/min for antipyrine. These experiments validate the applicability of the presented technique in in vivo studies.

The blood-brain barrier transport characteristics of racemic baclofen and the separate R- and S-enantiomers have been determined in vivo in rats by using the unit impulse response methodology. Transport rate was determined as blood-brain barrier clearance, the volume of plasma per unit time cleared of baclofen by transport across the blood-brain barrier. Plasma elimination kinetics and CSF elimination kinetics did not differ among racemic baclofen and the R- and S-enantiomers. Transport of each compound could be described by a linear V(t) curve, suggesting the absence of saturable transport processes in the concentration range studied. However, for R-baclofen the blood-brain barrier clearance (4.7 +/- 1.0 microliters/min, mean +/- SE; n = 6) and cumulative transported amount (0.085 +/- 0.007%; n = 6) were significantly higher than these values for the S-enantiomer (1.1 +/- 0.3 microliters/min, 0.031 +/- 0.005%; n = 6) and racemic baclofen (1.0 +/- 0.1 microliters/min, 0.036 +/- 0.003%; n = 6). These findings indicate that there is stereoselective transport of baclofen across the blood-brain barrier.

The mechanism of transport of baclofen, a centrally acting muscle relaxant, across the blood-brain barrier (BBB) was studied using an in vitro model. The model consisted of a monolayer of bovine brain endothelial cells grown in primary culture on a porous regenerated cellulose membrane. The transport of baclofen across the monolayer expressed time and concentration dependency and was saturable. Transport data were corrected for diffusion and fitted to the Michaelis-Menten Vmax model: Km = 58.5 microM, Vmax = 0.23 nmol/min. The results validate the use of the in vitro BBB model as described and support the hypothesis that baclofen penetrates the BBB by means of a carrier-mediated transport system.

The pharmacokinetic characteristics of desglycinamide-arginine vasopressin (DGAVP) with respect to its transport across the blood-brain barrier (BBB) were studied with the use of serial CSF sampling in an individual animal and the unit impulse response methodology. Transport rate is determined as BBB clearance, the volume of plasma per unit time cleared of the peptide by BBB transport, and the extent of transport as the percentage of the administered dose transported into the central nervous system. Plasma kinetics of DGAVP were shown to be linear within the dose range studied (50-150 micrograms), plasma mean residence time (MRT) being 18 +/- 4 min (mean +/- SE; n = 9). Elimination of DGAVP from CSF after icv administration was linear, with an MRT of 10 +/- 1 min (n = 9). After iv administration of 100 micrograms DGAVP, CSF concentrations were detectable for 90 min. Transport from plasma to the central nervous system was linear. The BBB transport clearance value was 1.0 +/- 0.3 microliters/min, and 0.026 +/- 0.007% of the administered dose was transported into the central nervous system. Results demonstrate that, within the concentration range studied, DGAVP is transported across the BBB by passive diffusion, although to a very low extent.

This review describes various aspects of the transport of drugs across the blood-brain barrier and comprises three parts. In this first part, the anatomical and physiological aspects of blood-brain transport are discussed. It appears that the blood-brain barrier has an anatomical basis at the endothelium of the capillary wall. This endothelium is characterized by the presence of very tight junctions. As a result, the transport by passive diffusion of drugs with a low lipophilicity, is restricted. For certain classes of closely related relatively hydrophilic compounds, however, the presence of specialized carrier systems has been demonstrated which may facilitate transport. Also evidence is presently available, that the permeability of the blood-brain barrier may be under active regulatory control. It is expected that improved knowledge of the anatomical and physiological aspects of the blood-brain barrier and its regulation will provide a scientific basis for the development of strategies to improve the transport of drugs into the central nervous system.