title: Molecular-weight-dependent, anionic-substrate-preferential transport of β-lactam antibiotics via multidrug resistance-associated protein 4.
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 blood-brain 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.
authors: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Shin-Ichi
authors: S
authors: Akanuma
authors: Yasuo
authors: Y
authors: Uchida
authors: Sumio
authors: S
authors: Ohtsuki
authors: Jun-ichi
authors: J
authors: Kamiie
authors: Masanori
authors: M
authors: Tachikawa
authors: Tetsuya
authors: T
authors: Terasaki
authors: Ken-ichi
authors: K
authors: Hosoya
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D015310:Cefotiam / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D015310:Cefotiam; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D047090:beta-Lactams; C073492:ABCC4 protein, human