Vol. 280, Issue 2, 551-560, 1997

Quantitative Evaluation of Brain Distribution and Blood-Brain Barrier Efflux Transport of Probenecid in Rats by Microdialysis: Possible Involvement of the Monocarboxylic Acid Transport System¹

Yoshiharu Deguchi, Kenji Nozawa, Shizuo Yamada, Yoshinari Yokoyama and Ryohei Kimura

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan

This study was performed to evaluate quantitatively the brain distribution and the efflux transport across the blood-brain barrier of probenecid, using in vivo microdialysis and in situ brain perfusion techniques. The brain interstitial fluid (ISF)-to-plasma cerebrospinal fluid (CSF)-to-plasma and brain tissue-to-plasma unbound concentration ratios of probenecid at steady state were less than unity, which suggests restricted distribution in the brain. An uphill concentration gradient from ISF to plasma and a downhill concentration gradient from CSF to ISF were observed. Kinetic analysis revealed that the efflux clearance from brain ISF to plasma (0.0373 ml/min/g brain) was significantly greater than the influx clearance from plasma to brain (0.00733 ml/min/g brain). The ratio of the ISF concentration (C_isf) to the plasma unbound concentration (C_p,f) of probenecid was increased 2- to 3-fold by salicylate (3.7 mM) and benzoate (3.6 mM), which are accepted as substrates of the monocarboxylic acid transport system, compared with the same ratio for the control. In addition, the ratio C_isf/C_p,f was increased by treatment with N-ethylmaleimide, a sulfhydryl-modifying agent, whereas p-aminohippuric acid and choline did not produce increasing effects on C_isf/C_p,f. These data suggest that the restricted distribution of probenecid in the brain may be ascribed to efficient efflux from the brain ISF, which may be regulated by the monocarboxylic acid transport system at a relatively high ISF concentration.