SELECTIVE BRAIN TO BLOOD EFFLUX TRANSPORT OF PARA-AMINOHIPPURIC ACID ACROSS THE BLOOD-BRAIN-BARRIER - IN-VIVO EVIDENCE BY USE OF THE BRAIN EFFLUX INDEX METHOD

Efflux transport of para-aminahippuric acid (PAH) across the blood-bra in barrier (BBB) has been demonstrated by use of the brain efflux inde x (BEI) method. PAH was eliminated from the ipsilateral cerebrum exten sively with an apparent efflux rate constant of 0.0587 (min(-1)) after microinjection into a cerebral cortex region termed Par2. This efflux transport showed a saturation with the Michaelis constant of approxim ately 400 mu M. No more than 3% dose of PAH and carboxyl-inulin, used as a reference compound showing limited permeability at the BBB, were found in the contralateral cerebrum, cerebellum or cerebrospinal fluid up to 20 min after administration, Under saturated conditions for car rier-mediated efflux of PAH via the blood-cerebrospinal fluid barrier, the BEI Value of PAH did not change significantly which suggested tha t blood-cerebrospinal fluid barrier was not responsible for the elimin ation of PAH from the brain after microinjection. No significant metab olism of PAH was demonstrated in the brain for at least 20 min after m icroinjection, and most of the radioactivity in the ipsilateral and co ntralateral carotid veins was as the intact form. With the distributio n volume of PAH, 0.800 ml/g brain, obtained from the brain slice uptak e experiment, the apparent efflux clearance was calculated as 46.9 mu l/min/g brain. In addition, the influx clearance of PAH across the BBB determined by the in vivo brain uptake index method was much smaller than the efflux clearance, which demonstrates that BBB transports PAH selectively from the brain to the circulating blood.