Comparative distribution of quinolone antibiotics in cerebrospinal fluid and brain in rats and dogs

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,u(CSF)) differed widely ranging from 0.11 (NFLX) to 1.0 (PFLX). About a 10-fold difference between compounds was also observed in the Kp,u(CSF) in rats; however, these values were 25 to 50% smaller than those in dogs. Similarly, the brain to unbound serum concentration ratio (Kp,u(Brain)) 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,u(Brain) and Kp,u(CSF) all increased as the lipophilicity of the compound increased (except the Kp,u(Brain) in dogs). We also found that the quinolones inhibited the saturable accumulation of [¹⁴C]FLRX (K(m) 660 μM) by the isolated rat choroid plexus. About a 20-fold difference among the apparent IC₅₀ values for FLRX transport was observed between NFLX (6000 μM) and PFLX (300 μM). 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,u(Brain) or Kp,u(CSF)) suggests a minor contribution of this efflux system to the CNS distribution of quinolones.