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

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 μM), cefazolin ( K m , 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.