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

Shin Ichi Akanuma, Ken Ichi Hosoya, Shingo Ito, Masanori Tachikawa, Tetsuya Terasaki, Sumio Ohtsuki

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)912-919
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume333
Issue number3
DOIs
Publication statusPublished - 2010 Jun

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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