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Molecular Pharmacology

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Research ArticleArticle

Involvement of MRP4 (ABCC4) in the Luminal Efflux of Ceftizoxime and Cefazolin in the Kidney

Lei Ci, Hiroyuki Kusuhara, Masashi Adachi, John D. Schuetz, Kenji Takeuchi and Yuichi Sugiyama
Molecular Pharmacology June 2007, 71 (6) 1591-1597; DOI: https://doi.org/10.1124/mol.106.031823
Lei Ci
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Hiroyuki Kusuhara
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Masashi Adachi
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John D. Schuetz
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Kenji Takeuchi
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Yuichi Sugiyama
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Abstract

The purpose of the present study was to investigate the role of multidrug resistance-associated protein 4 (MRP4) in the tubular secretion of cephalosporin antibiotics. Most of the injectable cephalosporins have an inhibitory effect on the ATP-dependent uptake of [3H]dehydroepiandrosterone sulfate by membrane vesicles expressing hMRP4, whereas cephaloridine, cefsulodin, and cefepime do not. Aminocephalosporins have a weak inhibitory effect. Significant ATP-dependent transport of ceftizoxime (Km, 18 μM), cefazolin (Km, 80 μM), cefotaxime, and cefmetazole has been observed only in the membrane vesicles expressing hMRP4. Ceftizoxime and cefazolin were given by a constant intravenous infusion to wild-type and Mrp4–/– mice. The steady-state plasma concentrations of ceftizoxime and cefazolin were unchanged in Mrp4–/– mice. The urinary recovery of ceftizoxime was significantly reduced in Mrp4–/– mice, whereas it was unchanged for cefazolin. The kidney-to-plasma concentration ratio of ceftizoxime and cefazolin was increased 2.0- and 2.7-fold in Mrp4–/– mice, respectively; thus, the renal clearance with regard to the kidney concentration was reduced in Mrp4–/– mice, to 7.5 and 34% of the corresponding control values, respectively. These results suggest that Mrp4 is involved in the tubular secretion of ceftizoxime and cefazolin, in concert with basolateral uptake transporters.

Footnotes

  • This work was supported by the Advanced and Innovational Research Program in Life Sciences from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to Y.S.); a Grant-in-Aid for Scientific Research on Priority Areas (KAKENHI 18059007 to H.K.); National Institutes of Health grants GM60904, ES058571, and CA23099 (to J.D.S.); Cancer Center support grant P30-CA21745 (to J.D.S.); and the American Lebanese-Syrian Associated Charities (to J.D.S.).

  • L.C. and H.K. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.031823.

  • ABBREVIATIONS: OAT, organic anion transporter; BBM, brush-border membrane; MRP, multidrug resistance-associated protein; DHEAS, dehydroepiandrosterone sulfate; GFP, green fluorescent protein; TS, Tris-sucrose; GFR, glomerular filtration rate; CL, clearance.

    • Received October 16, 2006.
    • Accepted March 2, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Involvement of MRP4 (ABCC4) in the Luminal Efflux of Ceftizoxime and Cefazolin in the Kidney

Lei Ci, Hiroyuki Kusuhara, Masashi Adachi, John D. Schuetz, Kenji Takeuchi and Yuichi Sugiyama
Molecular Pharmacology June 1, 2007, 71 (6) 1591-1597; DOI: https://doi.org/10.1124/mol.106.031823

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Research ArticleArticle

Involvement of MRP4 (ABCC4) in the Luminal Efflux of Ceftizoxime and Cefazolin in the Kidney

Lei Ci, Hiroyuki Kusuhara, Masashi Adachi, John D. Schuetz, Kenji Takeuchi and Yuichi Sugiyama
Molecular Pharmacology June 1, 2007, 71 (6) 1591-1597; DOI: https://doi.org/10.1124/mol.106.031823
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