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Research ArticleArticle

The Interaction and Transport of β-Lactam Antibiotics with the Cloned Rat Renal Organic Anion Transporter 1

Surawat Jariyawat, Takashi Sekine, Michio Takeda, Nopporn Apiwattanakul, Yoshikatsu Kanai, Samaisukh Sophasan and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics August 1999, 290 (2) 672-677;
Surawat Jariyawat
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Takashi Sekine
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Michio Takeda
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Nopporn Apiwattanakul
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Yoshikatsu Kanai
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Samaisukh Sophasan
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Hitoshi Endou
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Abstract

In the present study, we investigated the interactions between antibiotics, especially β-lactam antibiotics, and rat renal organic anion transporter 1 (OAT1). [14C]p-Aminohippurate (PAH) uptake via OAT1 expressed in Xenopus laevis oocytes was inhibited by all of the penicillins and cephalosporins tested. Penicillin G, carbenicillin, cephaloridine, cephalothin, cefazolin, and cephalexin inhibited [14C]PAH uptake via OAT1 in a competitive manner (Ki = 0.29–2.33 mM). Cinoxacin, a quinolone gyrase inhibitor, also inhibited PAH uptake via OAT1. Other antibiotics, such as gentamicin, streptomycin, and vancomycin, which do not contain anionic moieties, did not interact with OAT1. [3H]Penicillin G and [14C]cephaloridine were demonstrated to be transported via OAT1. Using the cells that stably expressed OAT1, we analyzed the cytotoxicity of several β-lactam antibiotics. Cells expressing OAT1 showed higher susceptibility to cephaloridine (a potentially nephrotoxic β-lactam antibiotic) toxicity than did control cells. The present study suggests that OAT1 is the major organic anion transporter in the kidney that is responsible for the renal secretion of antibiotics, especially that of β-lactam antibiotics. Furthermore, the culture cell system expressing OAT1 was revealed to be useful for the prediction of the nephrotoxicity of β-lactam antibiotics.

Footnotes

  • Send reprint requests to: Dr. Hitoshi Endou, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.

  • ↵1 This work was supported in part by grants from the Japanese Ministry of Education Science, Sports and Culture; Science Research Promotion Fund of the Japan Private School Promotion Foundation; Uehara Memorial Foundation; and Tokyo Biochemical Research Foundation.

  • Abbreviations:
    PAH
    p-aminohippurate
    OAT1
    organic anion transporter 1
    PCG
    penicillin G
    MRP2
    multidrug resistance-associated protein 2
    O.D.
    optical density
    • Received February 8, 1999.
    • Accepted April 13, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 2
1 Aug 1999
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Research ArticleArticle

The Interaction and Transport of β-Lactam Antibiotics with the Cloned Rat Renal Organic Anion Transporter 1

Surawat Jariyawat, Takashi Sekine, Michio Takeda, Nopporn Apiwattanakul, Yoshikatsu Kanai, Samaisukh Sophasan and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics August 1, 1999, 290 (2) 672-677;

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Research ArticleArticle

The Interaction and Transport of β-Lactam Antibiotics with the Cloned Rat Renal Organic Anion Transporter 1

Surawat Jariyawat, Takashi Sekine, Michio Takeda, Nopporn Apiwattanakul, Yoshikatsu Kanai, Samaisukh Sophasan and Hitoshi Endou
Journal of Pharmacology and Experimental Therapeutics August 1, 1999, 290 (2) 672-677;
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