In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin

The role of mdrla-encoded P-glycoprotein on transport of several fluoroquin olones across the blood-brain barrier was investigated. In vitro, P-glycopr otein substrates were selected by using a confluent monolayer of MDR1-LLC-P K1 cells. The inhibition of fluoroquinolones (100 muM) on transport of rhod amine-123 (1 muM) was compared with P-glycoprotein inhibitors verapamil (20 muM) and SDZ PSC 833 (2 muM) Subsequently, transport polarity of fluoroqui nolones was studied. Sparfloxacin showed the strongest inhibition (26%) and a large polarity in transport, by P-glycoprotein activity. In vivo, using mdrla (-/-) and wild-type mice, brain distribution of pefloxacin, norfloxac in, ciprofloxacin, fleroxacin and sparfloxacin was determined at 2, 4, and 6 h following intra-arterial infusion (50 nmol/min). Brain distribution of sparfloxacin was clearly higher in mdrla (-/-) mice compared with wild-type mice. Sparfloxacin was infused (50 nmol/min) for 1, 2, 3 and 4 h in which intracerebral microdialysis was performed. At 4 h, in vivo recovery (dynami c-no-net-flux method) was 6.5 +/- 2.2 and 1.5 +/- 0.5%; brain(ECF) concentr ations were 5.1 +/- 0.2 and 26 +/- 21 muM; and total brain concentrations w ere 7.2 +/-0.3 and 23 +/- 0.3 muM in wild-type and mdrla (-/-) mice, respec tively. Plasma concentrations were similar (18.4 +/- 0.7 and 17.9 +/- 0.5 m uM, respectively). In conclusion, sparfloxacin enters the brain poorly main ly because of P-glycoprotein activity at the blood-brain barrier. (C) 2000 Elsevier Science B.V. All rights reserved.