In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin.
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.
de Lange
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EC
Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Sylvius Laboratory, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands. l.lange@chem.leidenuniv.nl
Marchand
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van den Berg
D
D
van der Sandt
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IC
de Boer
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AG
Delon
A
A
Bouquet
S
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Couet
W
W
D042462:4-Quinolones; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000995:Antitubercular Agents / Q000493:pharmacokinetics; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D002939:Ciprofloxacin / Q000493:pharmacokinetics; D016576:Fleroxacin / Q000493:pharmacokinetics; D024841:Fluoroquinolones; D007261:Infusions, Intra-Arterial; D007668:Kidney; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017551:Microdialysis; D009643:Norfloxacin / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000378:metabolism; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013552:Swine; D014018:Tissue Distribution; D014162:Transfection; D015366:Pefloxacin
D042462:4-Quinolones; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D000995:Antitubercular Agents; D002939:Ciprofloxacin; D016576:Fleroxacin; D024841:Fluoroquinolones; D009643:Norfloxacin; D011994:Recombinant Proteins; D020112:Rhodamine 123; D015366:Pefloxacin; C061363:sparfloxacin