Molecular-weight-dependent, Anionic-substrate-preferential transport of β-lactam antibiotics via multidrug resistance-associated protein 4

Shin Ichi Akanuma, Yasuo Uchida, Sumio Ohtsuki, Jun Ichi Kamiie, Masanori Tachikawa, Tetsuya Terasaki, Ken Ichi Hosoya

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

β-Lactam antibiotics have cerebral and peripheral adverse effects. Multidrug resistance- associated protein 4 (MRP4) has been reported to transport several β-lactam antibiotics, and its expression at the bloodbrain barrier also serves to limit their distribution to the brain. Therefore, the purpose of this study was to clarify the structure-activity relationship of MRP4-mediated transport of β-lactam antibiotics using MRP4-expressing Sf9 membrane vesicles. The transport activity was evaluated as MRP4-mediated transport per MRP4 protein [nL/(min·fmol MRP4 protein)] based on measurement of MRP4 protein expression by means of liquid chromatography-tandem mass spectrometry. Cefotiam showed the greatest MRP4-mediated transport activity [8.90 nL/(min·fmol MRP4 protein)] among the β-lactam antibiotics examined in this study. Measurements of differential transport activity of MRP4 for various β-lactam antibiotics indicated that (i) cephalosporins were transported via MRP4 at a greater rate than were penams, β-lactamase inhibitors, penems, or monobactams; (ii) MRP4-mediated transport activity of anionic cephalosporins was greater than that of zwitterionic cephalosporins; and (iii) higher-molecular-weight anionic β-lactam antibiotics showed greater MRP4-mediated transport activity than lower-molecular-weight ones, whereas zwitterionic β-lactam antibiotics did not show molecular weight dependency of MRP4- mediated transport. These quantitative data should prove useful for understanding MRP-related adverse effects of β-lactam antibiotics and their derivatives.

Original languageEnglish
Pages (from-to)602-611
Number of pages10
JournalDrug metabolism and pharmacokinetics
Volume26
Issue number6
DOIs
Publication statusPublished - 2011

Keywords

  • ABC transporters
  • Antibiotics
  • Blood-brain barrier
  • Cephalosporins
  • HPLC
  • MRP
  • MRP4
  • Membrane permeability
  • Transporters

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Molecular-weight-dependent, Anionic-substrate-preferential transport of β-lactam antibiotics via multidrug resistance-associated protein 4'. Together they form a unique fingerprint.

Cite this