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Antimicrobial Agents and Chemotherapy, February 2003, p. 689-696, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.689-696.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Effects of Organic Anion, Organic Cation, and Dipeptide Transport Inhibitors on Cefdinir in the Isolated Perfused Rat Kidney

Christopher S. Lepsy,1,2,{dagger} Robert J. Guttendorf,1 Alan R. Kugler,1 and David E. Smith2*

Pfizer Global Research and Development, Ann Arbor, Michigan 48105,1 College of Pharmacy and Upjohn Center for Clinical Pharmacology, University of Michigan, Ann Arbor, Michigan 481092

Received 3 July 2002/ Returned for modification 13 October 2002/ Accepted 11 November 2002

Cefdinir (Omnicef; Abbott Laboratories) is a cephalosporin antibiotic primarily eliminated by the kidney. Nonlinear renal elimination of cefdinir has been previously reported. Cefdinir renal transport mechanisms were studied in the erythrocyte-free isolated perfused rat kidney. Studies were performed with drug-free perfusate and perfusate containing cefdinir alone to establish the baseline physiology and investigate cefdinir renal elimination characteristics. To investigate cefdinir renal transport mechanisms, inhibition studies were conducted by coperfusing cefdinir with inhibitors of the renal organic anion (probenecid), organic cation (tetraethylammonium), or dipeptide (glycylsarcosine) transport system. Cefdinir concentrations in biological samples were determined using reversed-phase high-performance liquid chromatography. Differences between treatments and controls were evaluated using analysis of variance and Dunnett's test. The excretion ratio (ER; the renal clearance corrected for the fraction unbound and glomerular filtration rate) for cefdinir was 5.94, a value indicating net renal tubular secretion. Anionic, cationic, and dipeptide transport inhibitors all significantly affected the cefdinir ER. With probenecid, the ER was reduced to 0.59, clearly demonstrating a significant reabsorptive component to cefdinir renal disposition. This finding was confirmed by glycylsarcosine studies, in which the ER was elevated to 7.95, indicating that reabsorption was mediated, at least in part, by the dipeptide transporter system. The effects of the organic cation tetraethylammonium, in which the ER was elevated to 7.53, were likely secondary in nature. The anionic secretory pathway was found to be the predominant mechanism for cefdinir renal excretion.

* Corresponding author. Mailing address: 4302A Upjohn Center, 1310 E. Catherine St., University of Michigan, Ann Arbor, MI 48109-0504. Phone: (734) 647-1431. Fax: (734) 763-3438. E-mail: smithb{at}umich.edu.

{dagger} Present address: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Ann Arbor, MI 48105. Phone: (734) 622-7075. Fax: (734) 622-5115. E-mail: christopher.lepsy{at}pfizer.com.

Antimicrobial Agents and Chemotherapy, February 2003, p. 689-696, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.689-696.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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