title: Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and cefazolin in the kidney.
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 [(3)H]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 (K(m), 18 microM), cefazolin (K(m), 80 microM), 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.
authors.affiliation: Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Ci
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Masashi
authors.initials: M
authors.lastname: Adachi
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Kenji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001692:Biological Transport; D002437:Cefazolin / Q000493:pharmacokinetics*; D015296:Ceftizoxime / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*
chemical_list: D002437:Cefazolin; D015296:Ceftizoxime; D027425:ATP-Binding Cassette, Sub-Family C Proteins