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

Eur J Pharm Sci. 2000 Dec;12(2):85-93. doi: 10.1016/s0928-0987(00)00149-4.

Abstract

The role of mdr1a-encoded P-glycoprotein on transport of several fluoroquinolones across the blood-brain barrier was investigated. In vitro, P-glycoprotein substrates were selected by using a confluent monolayer of MDR1-LLC-PK1 cells. The inhibition of fluoroquinolones (100 microM) on transport of rhodamine-123 (1 microM) was compared with P-glycoprotein inhibitors verapamil (20 microM) and SDZ PSC 833 (2 microM). Subsequently, transport polarity of fluoroquinolones was studied. Sparfloxacin showed the strongest inhibition (26%) and a large polarity in transport, by P-glycoprotein activity. In vivo, using mdr1a (-/-) and wild-type mice, brain distribution of pefloxacin, norfloxacin, 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 mdr1a (-/-) 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 (dynamic-no-net-flux method) was 6.5+/-2.2 and 1.5+/-0.5%; brain(ECF) concentrations were 5.1+/-0.2 and 26+/-21 microM; and total brain concentrations were 7.2+/-0.3 and 23+/-0.3 microM in wild-type and mdr1a (-/-) mice, respectively. Plasma concentrations were similar (18.4+/-0.7 and 17.9+/-0.5 microM, respectively). In conclusion, sparfloxacin enters the brain poorly mainly because of P-glycoprotein activity at the blood-brain barrier.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Quinolones*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / deficiency
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Anti-Infective Agents / administration & dosage
  • Anti-Infective Agents / pharmacokinetics*
  • Antitubercular Agents / pharmacokinetics
  • Biological Transport
  • Brain / metabolism*
  • Cell Line
  • Ciprofloxacin / pharmacokinetics
  • Fleroxacin / pharmacokinetics
  • Fluoroquinolones*
  • Infusions, Intra-Arterial
  • Kidney
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microdialysis
  • Norfloxacin / pharmacokinetics
  • Recombinant Proteins / metabolism
  • Rhodamine 123 / pharmacokinetics
  • Swine
  • Tissue Distribution
  • Transfection

Substances

  • 4-Quinolones
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Infective Agents
  • Antitubercular Agents
  • Fluoroquinolones
  • Recombinant Proteins
  • perfloxacin
  • Rhodamine 123
  • Ciprofloxacin
  • Norfloxacin
  • Fleroxacin
  • sparfloxacin