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 M), cefazolin (K m , 80 M), 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 Ϫ/Ϫ mice.The steady-state plasma concentrations of ceftizoxime and cefazolin were unchanged in Mrp4 Ϫ/Ϫ mice. The urinary recovery of ceftizoxime was significantly reduced in Mrp4 Ϫ/Ϫ 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 Ϫ/Ϫ mice, respectively; thus, the renal clearance with regard to the kidney concentration was reduced in Mrp4 Ϫ/Ϫ 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.

Identification of multidrug and toxin extrusion (MATE1 and MATE2-K) variants with complete loss of transport activity

“…For example, multidrug resistance-associated protein 4 (MRP4) was demonstrated to be responsible for the renal elimination of antiviral drugs, 6 diuretics 7 and cephalosporin antibiotics. 8 Human orthologs of the multidrug and toxin extrusion (MATE) family, members of which confer multidrug resistance on bacteria, were identified most recently, 9,10 and named MATE1 (SLC47A1) and MATE2-K (SLC47A2). Both transporters are expressed mainly in the renal brush border membranes, and are able to transport tetraethylammonium (TEA) utilizing an oppositely directed H + gradient as a driving force, 11 indicating that MATE1 and MATE2-K are H + /organic cation antiporters.…”

Pharmacokinetics and Pharmacogenomics of β-Lactam-Induced Neutropenia

“…MRP4 is an efflux transporter present on both on the apical membrane of renal proximal tubule cells as well as the surface of CD34 + stem cells and other bone marrow cells [8]. It has been shown that various β-lactam antibiotics are substrates of MRP4 using tandem mass spectrometry and in vitro studies of membrane vesicles expressing human MRP4 [10,11]. MRP4 also was demonstrated to be involved in the luminal efflux of ceftizoxime and cefazolin in the renal tubule of a mouse model; MRP4 knockout mice demonstrated higher renal concentrations of the cephalosporin antibiotics [11].…”

“…It has been shown that various β-lactam antibiotics are substrates of MRP4 using tandem mass spectrometry and in vitro studies of membrane vesicles expressing human MRP4 [10,11]. MRP4 also was demonstrated to be involved in the luminal efflux of ceftizoxime and cefazolin in the renal tubule of a mouse model; MRP4 knockout mice demonstrated higher renal concentrations of the cephalosporin antibiotics [11]. Additionally, MRP4 knockout mice have also demonstrated bone marrow aplasia and enhanced hematopoietic toxicity with exposure to other studied drugs, such as thiopurine, suggesting that MRP4 may provide progenitor cell specific protection in its role as a surface cell transporter [14,15].…”

“…MRP4 is also expressed on CD34 + stem cells and in other bone marrow cells [8]. β-lactam antibiotics are known substrates of both MRP4 and OAT, and mouse models lacking these MRP4 and OAT3 have demonstrated increased renal concentrations and increased plasma concentrations of β-lactam antibiotics, respectively [10][11][12][13] there is also evidence that MRP4 provides protection against hematopoietic toxicity secondary to thiopurine [14,15]. It is interesting to postulate that MRP4 and OATs protect against hematopoietic toxicity by controlling blood and renal levels of β-lactam antibiotics.…”

Nanoscale drug delivery systems and the blood–brain barrier

“…32 Moreover, this enzyme pumps out the diuretics furosemide and trichlorometazide 33 and the antibiotics cefazolin and cefotaxime. 34 The antitumor compounds methotrexate, 35 mitoxantrone, 36 topotecan, and imatinib, 37 the anthracyclines daunorubicin and doxorubicin, 38 as well as prazosin and nitrofurantoin, are substrates for BCRP/ABCG2. 30,39 The family of solute carrier (SLC) transporters is an important component of the organic anion efflux transport system of ECs.…”