TY - JOUR T1 - Kinetic Evidence for Active Efflux Transport across the Blood-Brain Barrier of Quinolone Antibiotics JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 293 LP - 304 VL - 283 IS - 1 AU - Tsuyoshi Ooie AU - Tetsuya Terasaki AU - Hiroshi Suzuki AU - Yuichi Sugiyama Y1 - 1997/10/01 UR - http://jpet.aspetjournals.org/content/283/1/293.abstract N2 - A distributed model has been used to clarify the mechanism of the restricted and differential distribution of the quinolone antibiotics in the rat central nervous system (CNS). The symmetrical permeability clearances across the blood-brain barrier (BBB), PSBBB, and across the blood-cerebrospinal fluid barrier (BCSFB), PSCSF, and the active efflux clearances across the BBB, PSBBB,eff, were obtained from a nonlinear least squares regression analysis combined with the fast inverse Laplace transforming program for invivo data. The values of PSBBB,eff were 10- to 260-fold greater than those of PSBBB, providing kinetic evidence to support the hypothesis that a significant efflux transport across the BBB is responsible for the limited distribution of quinolones in brain tissue. Moreover, by simulation studies, we could demonstrate the concentration profiles in the brain as a function of the distance from the ependymal surface. However, active efflux transport across the BCSFB has been suggested to have only a slight effect on the apparent elimination from the cerebrospinal fluid. Comparing the apparent brain tissue-to-unbound serum concentration ratio at steady state, it has been suggested that the net flux across the BBB, i.e., the ratio of PSBBB to the sum of PSBBB and PSBBB,eff, is a determinant for the differential distribution of these quinolones in brain tissue. Such a putative active efflux transport system would play a significant role in decreasing the brain interstitial fluid concentration of quinolones. The American Society for Pharmacology and Experimental Therapeutics ER -