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First published on March 7, 2007; DOI: 10.1124/mol.106.031823

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Received for publication October 17, 2006.
Revised February 11, 2007.
Accepted for publication March 2, 2007.

Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and cefazolin in the kidney

Lei Ci 1, Hiroyuki Kusuhara 1, Masashi Adachi 2, John D. Schuetz 2, Kenji Takeuchi 1, Yuichi Sugiyama 1*

1 The University of Tokyo 2 St. Jude Children's Research Hospital

* Address correspondence to: E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

Abstract

The purpose of the present study is to investigate the role of MRP4 in the tubular secretion of cephalosporin antibiotics. Most of the injectable cephalosporins have an inhibitory effect on the ATP-dependent uptake of [3H]DHEAS by membrane vesicles expressing hMRP4, while cefaloridine, 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, while 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, and 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.


Key words: Organic anion, Antibiotic mechanisms


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