Involvement of multidrug resistance-associated protein 4 in efflux transport of prostaglandin E(2) across mouse blood-brain barrier and its inhibition by intravenous administration of cephalosporins.
Prostaglandin E(2) (PGE(2)) acts as a modulator of synaptic signaling and excitability in the brain. Because PGE(2) is barely inactivated enzymatically in adult brain, its brain level is considered to be controlled by efflux transport across the blood-brain barrier (BBB). The purpose of the present study was to clarify the efflux transport of PGE(2) at the BBB and the interaction of various drugs with this process. [(3)H]PGE(2) was eliminated from brain across the BBB with a half-life of 16.3 min, and the elimination was inhibited by 3 mM unlabeled PGE(2). Multidrug resistance-associated protein 4 (MRP4/ABCC4) was reported to be localized at the luminal membrane of the BBB. MRP4-expressing membrane vesicles showed significant uptake of [(3)H]PGE(2) and the uptake was inhibited by cefmetazole with an IC(50) value of 10.2 microM. At the concentration of 20 microM, several drugs, including cefazolin, cefotaxime, ceftriaxone, and ketoprofen, significantly inhibited [(3)H]PGE(2) uptake into MRP4-expressing membrane vesicles. Using the brain efflux index method, preadministration of cefmetazole, cefazolin, ceftriaxone, and cefotaxime was found to inhibit [(3)H]PGE(2) efflux from brain across the BBB. Furthermore, intravenous administration of the cefmetazole dose dependently reduced [(3)H]PGE(2) elimination across the BBB (ID(50) = 120 mg/kg). These results indicate that PGE(2) is eliminated from the brain by MRP4-mediated efflux transport at the BBB, and peripheral administration of cefmetazole decreases the efflux transport of PGE(2) at the BBB; this interaction may influence brain function.
Akanuma
Shin-ichi
S
Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Hosoya
Ken-ichi
K
Ito
Shingo
S
Tachikawa
Masanori
M
Terasaki
Tetsuya
T
Ohtsuki
Sumio
S
D000465:Algorithms; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000502:physiology; D002511:Cephalosporins / Q000008:administration & dosage / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007267:Injections; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002511:Cephalosporins; D015232:Dinoprostone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C489540:Abcc4 protein, mouse