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Research ArticleArticle

Impact of Genetic Knockout of PEPT2 on Cefadroxil Pharmacokinetics, Renal Tubular Reabsorption, and Brain Penetration in Mice

Hong Shen, Scott M. Ocheltree, Yongjun Hu, Richard F. Keep and David E. Smith
Drug Metabolism and Disposition July 2007, 35 (7) 1209-1216; DOI: https://doi.org/10.1124/dmd.107.015263
Hong Shen
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Scott M. Ocheltree
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Yongjun Hu
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Richard F. Keep
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David E. Smith
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Abstract

The aim of this study was to examine the role of PEPT2, a proton-coupled oligopeptide transporter of the SLC15 family, on the disposition of the antibiotic cefadroxil in the body, particularly the kidney and brain. Pharmacokinetic, tissue distribution, and renal clearance studies were performed in wild-type and PEPT2 null mice after intravenous bolus administration of [3H]cefadroxil at 1, 12.5, 50, and 100 nmol/g body weight. Studies were also performed in the absence and presence of probenecid and quinine. Cefadroxil disposition kinetics was clearly nonlinear over the dose range studied (1–100 nmol/g), which was attributed to both saturable renal tubular secretion and reabsorption of the antibiotic. After an intravenous bolus dose of 1 nmol/g cefadroxil, PEPT2 null mice exhibited a 3-fold greater total clearance and 3-fold lower systemic concentrations of drug compared with wild-type animals. Renal clearance studies further demonstrated that the renal reabsorption of cefadroxil was almost completely abolished in PEPT2 null versus wild-type mice (3% versus 70%, p < 0.001). Of the 70% of cefadroxil reabsorbed in wild-type mice, PEPT2 accounted for 95% and PEPT1 accounted for 5% of reabsorbed substrate. Tissue distribution studies indicated that PEPT2 had a dramatic effect on cefadroxil tissue exposure, especially in brain where the cerebrospinal fluid (CSF)-to-blood concentration ratio of cefadroxil was 6-fold greater in PEPT2 null mice compared with wild-type animals. These findings demonstrate that renal PEPT2 is almost entirely responsible for the reabsorption of cefadroxil in kidney and that choroid plexus PEPT2 limits the exposure of cefadroxil (and perhaps other aminocephalosporins) in CSF.

Footnotes

  • This work was partially funded by National Institutes of Health Grants R01 GM035498 (D.E.S.), and R01 NS034709 and P01 HL018575 (R.F.K.). H.S. was the recipient of a Predoctoral Fellowship from Rackham Graduate School, University of Michigan. S.M.O. was supported by an American Foundation for Pharmaceutical Education Predoctoral Fellowship, by the Pharmacological Sciences Training Program of the National Institutes of Health Grant T32 GM007767, and by a Predoctoral Fellowship from Rackham Graduate School, University of Michigan.

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

  • doi:10.1124/dmd.107.015263.

  • ABBREVIATIONS: POT, proton-coupled oligopeptide transporter; CNS, central nervous system; CSF, cerebrospinal fluid; ER, excretion ratio; GFR, glomerular filtration rate; GlySar, glycylsarcosine; OAT, organic anion transporter; OCT, organic cation transporter; AUC, area under the plasma concentration-time curve; CL, clearance; ANOVA, analysis of variance.

  • ↵1 Current affiliation: Dev MAP, Bristol-Myers Squibb, Princeton, New Jersey.

  • ↵2 Current affiliation: Drug Disposition and Global PK/PD, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.

    • Received February 22, 2007.
    • Accepted April 19, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (7)
Drug Metabolism and Disposition
Vol. 35, Issue 7
1 Jul 2007
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Research ArticleArticle

Impact of Genetic Knockout of PEPT2 on Cefadroxil Pharmacokinetics, Renal Tubular Reabsorption, and Brain Penetration in Mice

Hong Shen, Scott M. Ocheltree, Yongjun Hu, Richard F. Keep and David E. Smith
Drug Metabolism and Disposition July 1, 2007, 35 (7) 1209-1216; DOI: https://doi.org/10.1124/dmd.107.015263

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Research ArticleArticle

Impact of Genetic Knockout of PEPT2 on Cefadroxil Pharmacokinetics, Renal Tubular Reabsorption, and Brain Penetration in Mice

Hong Shen, Scott M. Ocheltree, Yongjun Hu, Richard F. Keep and David E. Smith
Drug Metabolism and Disposition July 1, 2007, 35 (7) 1209-1216; DOI: https://doi.org/10.1124/dmd.107.015263
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