STUDY ON BRAIN INTERSTITIAL FLUID DISTRIBUTION AND BLOOD-BRAIN-BARRIER TRANSPORT OF BACLOFEN IN RATS BY MICRODIALYSIS

Purpose. This study was performed to examine the distribution in the b rain interstitial fluid (ISF) and the blood-brain barrier (BBB) transp ort of baclofen in rats by a microdialysis technique. Methods. Followi ng an i.v. bolus administration and/or the constant i.v. infusion of b aclofen to the microdialysis cannula-bearing anesthetized rats, the co ncentrations of baclofen in the hippocampal ISF, whole brain tissue, c erebrospinal fluid (CSF), and plasma were determined by high-performan ce liquid chromatography (HPLC). Data were kinetically analyzed to est imate the transport parameters, i.e., the influx clearance (CL(in)) fr om plasma to brain and the efflux rate constant (k(eff)) from brain to plasma, and the steady-state volume of distribution in the brain (V-d ). Results. The concentrations of baclofen in ISF, whole brain tissue, and CSF at the pseudo-steady state were almost 30-fold lower than the plasma unbound concentration, suggesting the restricted distribution of baclofen in the brain. The estimated values of CL(in) and k(eff) we re 0.00157 +/- 0.00076 ml/min/g of brain and 0.0872 +/- 0.0252 min(-1) , respectively. The efflux clearance (CL(out)) calculated by multiplyi ng k(eff) by V-d (0.816 +/- 0.559 ml/g of brain) was 0.0712 +/- 0.0529 ml/min/g of brain, and it was significantly 40-fold greater than the CL(in) value and fully greater than the convective flow in ISF. Furthe rmore, no significant concentration gradient was observed between ISF and CSF. These results suggest that the CL(out) value mainly reflects the efflux clearance through the BBB. Additionally, the hippocampal IS F/plasma concentration ratio of baclofen was markedly increased by bot h systemic administration of probenecid and its direct instillation in to ISF. Conclusions. The restricted distribution of baclofen in the br ain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.