Involvement of multidrug resistance-associated protein 4 in efflux transport of prostaglandin E₂ across mouse blood-brain barrier and its inhibition by intravenous administration of cephalosporins

Prostaglandin E₂ (PGE₂) acts as a modulator of synaptic signaling and excitability in the brain. Because PGE₂ 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. [³H]PGE₂ was eliminated from brain across the BBB with a half-life of 16.3 min, and the elimination was inhibited by 3 mM unlabeled PGE₂. 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 [³H]PGE₂ and the uptake was inhibited by cefmetazole with an IC₅₀ value of 10.2 μM. At the concentration of 20 μM, several drugs, including cefazolin, cefotaxime, ceftriaxone, and ketoprofen, significantly inhibited [³H]PGE₂ uptake into MRP4-expressing membrane vesicles. Using the brain efflux index method, preadministration of cefmetazole, cefazolin, ceftriaxone, and cefotaxime was found to inhibit [ ³H]PGE₂ efflux from brain across the BBB. Furthermore, intravenous administration of the cefmetazole dose dependently reduced [ ³H]PGE₂ elimination across the BBB (ID₅₀ = 120 mg/kg). These results indicate that PGE₂ is eliminated from the brain by MRP4-mediated efflux transport at the BBB, and peripheral administration of cefmetazole decreases the efflux transport of PGE₂ at the BBB; this interaction may influence brain function.