Ooie T, Suzuki H, Terasaki T, Sugiyama Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Pharmacol Exp Ther. 1996 Aug;278(2):590-6.
The distribution of the quinolone antibiotics, norfloxacin (NFLX), AM-1155, fleroxacin (FLRX), ofloxacin, sparfloxacin (SPFX) and pefloxacin (PFLX), in the central nervous system (CNS) was investigated in dogs and rats. In dogs, the steady-state cerebrospinal fluid (CSF) to unbound serum concentration ratio (Kp,uCSF) differed widely ranging from 0.11 (NFLX) to 1.0 (PFLX). About a 10-fold difference between compounds was also observed in the Kp,uCSF in rats; however, these values were 25 to 50% smaller than those in dogs. Similarly, the brain to unbound serum concentration ratio (Kp,uBrain) of quinolones differed widely ranging from 0.15 (NFLX) to 1.5 (SPFX) in dogs and 0.04 (NFLX) to 0.33 (FLRX) in rats. The steady-state concentration ratio between CSF and brain tissue exhibited a 3-fold difference among quinolones (0.5 for PFLX to 1.6 for SPFX) in dogs, whereas, these values were all close to unity in rats. Kp,uBrain and Kp,uCSF all increased as the lipophilicity of the compound increased (except the Kp,uBrain in dogs). We also found that the quinolones inhibited the saturable accumulation of [14C]FLRX (Km 660 microM) by the isolated rat choroid plexus. About a 20-fold difference among the apparent IC50 values for FLRX transport was observed between NFLX (6000 microM) and PFLX (300 microM). The absence of a negative correlation between the affinity of the quinolones for this transport system, which in turn represents the efflux clearance from the CSF, and their in vivo distribution in rat CNS (Kp,uBrain or Kp,uCSF) suggests a minor contribution of this efflux system to the CNS distribution of quinolones.
研究了喹诺酮类抗生素诺氟沙星（NFLX）、AM - 1155、氟罗沙星（FLRX）、氧氟沙星、司帕沙星（SPFX）和培氟沙星（PFLX）在犬和大鼠中枢神经系统（CNS）中的分布情况。在犬中，稳态脑脊液（CSF）与未结合血清浓度比（Kp,uCSF）差异很大，范围从0.11（NFLX）到1.0（PFLX）。在大鼠的Kp,uCSF中也观察到不同化合物之间存在约10倍的差异；然而，这些值比犬中的值小25%至50%。同样，喹诺酮类药物的脑与未结合血清浓度比（Kp,uBrain）在犬中差异很大，范围从0.15（NFLX）到1.5（SPFX），在大鼠中为0.04（NFLX）到0.33（FLRX）。犬中喹诺酮类药物的脑脊液与脑组织稳态浓度比在不同药物之间相差3倍（培氟沙星为0.5，司帕沙星为1.6），而在大鼠中这些值都接近1。Kp,uBrain和Kp,uCSF均随着化合物亲脂性的增加而升高（犬中的Kp,uBrain除外）。我们还发现喹诺酮类药物抑制了离体大鼠脉络丛对[14C]FLRX（Km 660 microM）的饱和摄取。诺氟沙星（6000 microM）和培氟沙星（300 microM）之间的FLRX转运表观IC50值相差约20倍。喹诺酮类药物对该转运系统的亲和力（这反过来代表从脑脊液中的外流转运清除率）与其在大鼠中枢神经系统中的体内分布（Kp,uBrain或Kp,uCSF）之间不存在负相关，这表明该外流转运系统对喹诺酮类药物在中枢神经系统中的分布贡献较小。
