Abstract
Prostaglandin E2 (PGE2) acts as a modulator of synaptic signaling and excitability in the brain. Because PGE2 is hardly 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 PGE2 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, pre-administration of cefmetazole, cefazolin, ceftriaxone and cefotaxime was found to inhibit [3H]PGE2 efflux from brain across the BBB. Furthermore, intravenous administration of 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.
Footnotes
- Received December 28, 2009.
- Revision received February 26, 2010.
- Accepted February 26, 2010.
- The American Society for Pharmacology and Experimental Therapeutics