title: Transport of gatifloxacin involves Na+/Ca2+ exchange and excludes P-glycoprotein and multidrug resistance associated-proteins in primary cultured rat brain endothelial cells.
abstract: The characteristics of gatifloxacin transport across blood brain barrier were investigated using primary cultured rat brain microvessel endothelial cells (rBMECs) as an in vitro model. Gatifloxacin uptake by rBMECs was time-, temperature- and energy-dependent. Gatifloxacin uptake by rBMECs was not influenced by P-glycoprotein (P-GP) inhibitor cyclosporine A or multidrug resistance associated-proteins (MRPs) inhibitor probenecid. However, verapamil inhibited the uptake in a concentration-dependent manner. Transendothelial transport study showed that transport of gatifloxacin across rBMEC monolayer was bidirectional, verapamil concentration-dependently inhibited transport from the apical to basolateral side, but did not significantly affect transport from basolateral to apical side. Gatifloxacin uptake was decreased in Ca(2+)-deprived medium but increased in Mg(2+)-deprived medium significantly. Furthermore, organic Ca(2+) channel blockers nifedipine and diltiazem had no effect on gatifloxacin uptake, but inorganic Ca(2+) channel blockers Ni(2+) and Mg(2+) inhibited the gatifloxacin uptake. The present study suggests that gatifloxacin transport across rBMECs involves a Na(+)/Ca(2+) exchange mechanism and extracellular Ca(2+) but not P-GP and MRPs.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Guang Ji
authors.initials: GJ
authors.lastname: Wang
authors.forename: Xiao Dong
authors.initials: XD
authors.lastname: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D002118:Calcium / Q000172:deficiency / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D024841:Fluoroquinolones / Q000378:metabolism*; D000077734:Gatifloxacin; D008274:Magnesium / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D002118:Calcium; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D008274:Magnesium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012964:Sodium