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

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Ci L, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y

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

Mol Pharmacol. 2007 Jun;71(6):1591-7. Epub 2007 Mar 7.

PubMed ID

17344354 [ View in PubMed

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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 [(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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cefazolin	Multidrug resistance-associated protein 4	Protein	Humans	Unknown	Substrate	Details