Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics.

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), PS(BBB), and across the blood-cerebrospinal fluid barrier (BCSFB), PS(CSF), and the active efflux clearances across the BBB, PS(BBB,eff), were obtained from a nonlinear least squares regression analysis combined with the fast inverse Laplace transforming program for in vivo data. The values of PS(BBB,eff) were 10- to 260-fold greater than those of PS(BBB), 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, ie., the ratio of PS(BBB) to the sum of PS(BBB) and PS(BBB,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.