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Research ArticleArticle

INTERACTIONS OF AMOXICILLIN AND CEFACLOR WITH HUMAN RENAL ORGANIC ANION AND PEPTIDE TRANSPORTERS

Meng Li, Gail D. Anderson, Brian R. Phillips, Wei Kong, Danny D. Shen and Joanne Wang
Drug Metabolism and Disposition April 2006, 34 (4) 547-555; DOI: https://doi.org/10.1124/dmd.105.006791
Meng Li
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Gail D. Anderson
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Brian R. Phillips
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Wei Kong
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Danny D. Shen
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Joanne Wang
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Abstract

Amoxicillin and cefaclor are two of the widely used β-lactam antibiotics in the treatment of urinary tract infections. Both drugs are eliminated mainly by the kidney and rely on renal excretion to exert their antibacterial activities in the urinary tract. Previous studies have suggested the involvement of organic anion and oligopeptide transporters in membrane transport of β-lactams. The objective of the current study was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established Madin-Darby canine kidney cell lines stably expressing highly functional hOAT1, hPepT1, and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated [3H]para-aminohippuric acid uptake (Ki = 11.0 and 1.15 mM, respectively). However, our uptake study revealed that neither drug was transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated [3H]glycylsarcosine uptake (Ki = 733 and 65 μM, respectively), whereas much lower affinity for hPepT1 was observed with both antibiotics. Direct uptake studies demonstrated that amoxicillin and cefaclor were transported by hPepT1 and hPepT2. Kinetic analysis showed that hPepT2-mediated uptake of both drugs was saturable with Km of 1.04 mM for amoxicillin and 70.2 μM for cefaclor. hPepT2, and to a lesser extent hPepT1, may play an important role in apical transport of amoxicillin and cefaclor in the renal tubule. hOAT1, in contrast, is not involved in basolateral uptake of these antibiotics.

Footnotes

  • This work was partially funded by National Institutes of Health Grants AT002077 (G.D.A.), GM66233 (J.W.), and the University of Washington National Institute of Environmental Health Sciences (NIEHS)-sponsored Center for Ecogenetics and Environmental Health Grant NIEHS P30ES07033 (J.W.). M.L. is a recipient of the William E. Bradley Endowed Fellowship from School of Pharmacy, University of Washington.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.006791.

  • ABBREVIATIONS: UTI, urinary tract infection; hPepT1, human peptide transporter 1; hPepT2, human peptide transporter 2; GFR, glomerular filtration rate; OAT, organic anion transporter; hOAT1, human organic anion transporter 1; Gly-Sar, glycylsarcosine; PAH, para-aminohippuric acid; YFP, yellow fluorescence protein; MDCK, Madin-Darby canine kidney; RFP, red fluorescence protein; MES, 4-morpholineethanesulfonic acid; LC/MS, liquid chromatography/mass spectrometry; MSD, mass selective detector.

    • Received August 2, 2005.
    • Accepted January 18, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (4)
Drug Metabolism and Disposition
Vol. 34, Issue 4
1 Apr 2006
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Research ArticleArticle

INTERACTIONS OF AMOXICILLIN AND CEFACLOR WITH HUMAN RENAL ORGANIC ANION AND PEPTIDE TRANSPORTERS

Meng Li, Gail D. Anderson, Brian R. Phillips, Wei Kong, Danny D. Shen and Joanne Wang
Drug Metabolism and Disposition April 1, 2006, 34 (4) 547-555; DOI: https://doi.org/10.1124/dmd.105.006791

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Research ArticleArticle

INTERACTIONS OF AMOXICILLIN AND CEFACLOR WITH HUMAN RENAL ORGANIC ANION AND PEPTIDE TRANSPORTERS

Meng Li, Gail D. Anderson, Brian R. Phillips, Wei Kong, Danny D. Shen and Joanne Wang
Drug Metabolism and Disposition April 1, 2006, 34 (4) 547-555; DOI: https://doi.org/10.1124/dmd.105.006791
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