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

• Published in: European journal of pharmaceutical sciences 2000-12, Vol.12 (2), p.85-93
• Main Authors: de Lange, Elizabeth C.M., Marchand, Sandrine, van den Berg, Dirk-Jan, van der Sandt, Inez C.J., de Boer, Albertus G., Delon, Annie, Bouquet, Serge, Couet, William
• Format: Article
• Language: English
• Subjects: 4-Quinolones; Animals; Anti-Infective Agents - administration & dosage; Anti-Infective Agents - pharmacokinetics; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - pharmacokinetics; 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; Biological and medical sciences; Biological Transport; Blood–brain barrier; Brain - metabolism; Cell Line; Ciprofloxacin - pharmacokinetics; Dynamic-no-net-flux; Fleroxacin - pharmacokinetics; Fluoroquinolones; In vitro transport; In vivo recovery; Infusions, Intra-Arterial; Intracerebral microdialysis; Kidney; LLC-PK1 cells; mdr1a (−/−) mice; Medical sciences; Mice; Mice, Inbred Strains; Mice, Knockout; Microdialysis; Norfloxacin - pharmacokinetics; P-Glycoprotein; Pefloxacin; Pharmacology. Drug treatments; Recombinant Proteins - metabolism; Rhodamine 123 - pharmacokinetics; Sparfloxacin; Swine; Tissue Distribution; Transfection
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/S0928-0987(00)00149-4

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 μM) on transport of rhodamine-123 (1 μM) was compared with P-glycoprotein inhibitors verapamil (20 μM) and SDZ PSC 833 (2 μM). 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 μM; and total brain concentrations were 7.2±0.3 and 23±0.3 μM in wild-type and mdr1a (−/−) mice, respectively. Plasma concentrations were similar (18.4±0.7 and 17.9±0.5 μM, respectively). In conclusion, sparfloxacin enters the brain poorly mainly because of P-glycoprotein activity at the blood–brain barrier.