Uptake and efflux of quinacrine, a candidate for the treatment of prion diseases, at the blood-brain barrier.
1. A clinical trial of quinacrine in patients with Creutzfeldt-Jakob disease is now in progress. The permeability of drugs through the blood-brain barrier (BBB) is a determinant of their therapeutic efficacy for prion diseases. The mechanism of quinacrine transport across the BBB was investigated using mouse brain endothelial cells (MBEC4). 2. The permeability of quinacrine through MBEC4 cells was lower than that of sodium fluorescein, a BBB-impermeable marker. The basolateral-to-apical transport of quinacrine was greater than its apical-to-basolateral transport. In the presence of P-glycoprotein (P-gp) inhibitor, cyclosporine or verapamil, the apical-to-basolateral transport of quinacrine increased. The uptake of quinacrine by MBEC4 cells was enhanced in the presence of cyclosporine or verapamil. 3. Quinacrine uptake was highly concentrative, this event being carried out by a saturable and carrier-mediated system with an apparent Km of 52.1 microM. Quinacrine uptake was insensitive to Na+-depletion and changes in the membrane potential and sensitive to changes in pH. This uptake was decreased by tetraethylammonium and cimetidine, a substrate and an inhibitor of organic cation transporters, respectively. 4. These findings suggest that quinacrine transport at the BBB is mediated by the efflux system (P-gp) and the influx system (organic cation transporter-like machinery).
Dohgu
Shinya
S
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Yamauchi
Atsushi
A
Takata
Fuyuko
F
Sawada
Yasufumi
Y
Higuchi
Shun
S
Naito
Mikihiko
M
Tsuruo
Takashi
T
Shirabe
Susumu
S
Niwa
Masami
M
Katamine
Shigeru
S
Kataoka
Yasufumi
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D027682:Cation Transport Proteins / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002927:Cimetidine / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019793:Fluorescein / Q000493:pharmacokinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017096:Prion Diseases / Q000188:drug therapy; D011796:Quinacrine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019789:Tetraethylammonium / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027682:Cation Transport Proteins; D019789:Tetraethylammonium; D002927:Cimetidine; D016572:Cyclosporine; D014700:Verapamil; D011796:Quinacrine; D019793:Fluorescein