Multiple drug transporters contribute to the brain transfer of levofloxacin

AIMS: The aim of this study was to assess the influence of the major transporters at blood–brain barrier and blood–cerebrospinal fluid barrier on levofloxacin (LVFX) pharmacokinetics in rat. To explore the different effects of transporters on drug concentrations in cerebrospinal fluid (CSF) and brain extracellular fluid (ECF). METHODS: High‐performance liquid chromatography coupled with microdialysis was used to continuously and synchronously measure unbound concentrations of LVFX in rat blood, hippocampal ECF, and lateral ventricle CSF for comprehensive characterization of brain pharmacokinetics. The role of transporters in the brain efflux mechanism of LVFX was analyzed in the absence and presence of various transporter inhibitors. RESULTS: Following LVFX (50 mg/kg) administration, the unbound partition coefficient of LVFX in brain ECF and CSF (K (p,uu,ECF) and K (p,uu,CSF)) were 34.0 ± 1.7% and 41.2 ± 2.4%, respectively. When probenecid was coadministered with LVFX, the AUC and the mean residence time (MRT) in rat blood increased significantly (p < 0.05). After MK571 intervention, 1.35‐fold and 1.16‐fold increases in K (p,uu,ECF) and K (p,uu,CSF) were observed, respectively (p < 0.05). Treatment with Ko143 increased the levels of LVFX in brain ECF. The difference in LVFX concentration in brain ECF and CSF was <3‐fold with or without treatment with transporter inhibitors. CONCLUSION: Efflux of LVFX from the central nervous system (CNS) involves multidrug resistance‐associated proteins (MRPs), breast cancer resistance protein (BCRP), and organic anion transporters (OATs). MRPs play an important role in mediating the brain/CSF‐to‐blood efflux of LVFX. LVFX concentrations in CSF can be used as a surrogate to predict the concentrations inside brain parenchyma.