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Relevance of PepT1 in the Intestinal Permeability and Oral Absorption of Cefadroxil

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ABSTRACT

Purpose

To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug cefadroxil.

Methods

The effective permeability (P eff ) of cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of cefadroxil were also examined after oral gavage.

Results

The P eff (cm/s) of cefadroxil in wild-type mice was 0.49 × 10−4 in duodenum, 0.80 × 10−4 in jejunum, 0.88 × 10−4 in ileum and 0.064 × 10−4 in colon. The P eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003 × 10−4, 0.090 × 10−4, 0.042 × 10−4 and 0.032 × 10−4, respectively. Jejunal uptake of cefadroxil was saturable (Km = 2–4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of cefadroxil after oral dosing.

Conclusions

The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of cefadroxil as well as its enhanced oral drug performance.

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM035498] (to D.E.S.).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA

    Maria M. Posada & David E. Smith

  2. Department of Pharmaceutical Sciences, University of Michigan, 4742C Medical Sciences II, 1150 W. Medical Center Drive, Ann Arbor, Michigan, 48109-5633, USA

    David E. Smith

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  1. Maria M. Posada
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Correspondence to David E. Smith.

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Posada, M.M., Smith, D.E. Relevance of PepT1 in the Intestinal Permeability and Oral Absorption of Cefadroxil. Pharm Res 30, 1017–1025 (2013). https://doi.org/10.1007/s11095-012-0937-8

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  • DOI: https://doi.org/10.1007/s11095-012-0937-8

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